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Physicochemical and Pharmacokinetic Analysis of Anacardic Acid Derivatives

Fahmina Zafar*

Fahmina Zafar

Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India

*E-mail: [email protected] (F.Z.).
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http://orcid.org/0000-0001-5454-3981
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Anjali Gupta*

Anjali Gupta

Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India

*E-mail: [email protected] (A.G.).
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Karthick Thangavel

Karthick Thangavel

Department of Physics, School of Electrical and Electronics Engineering, SASTRA Deemed University, Thanjavur 613 401, Tamil Nadu, India

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Kavita Khatana

Kavita Khatana

Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India

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Ali Alhaji Sani

Ali Alhaji Sani

Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India

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Anujit Ghosal

Anujit Ghosal

Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India

Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India

School of Life Sciences, Beijing Institute of Technology, Beijing 100811, China

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Poonam Tandon

Poonam Tandon

Department of Physics, University of Lucknow, Lucknow 226007, India

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http://orcid.org/0000-0002-8120-0498
, and
Nahid Nishat*

Nahid Nishat

Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India

*E-mail: [email protected] (N.N.).
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Cite this: ACS Omega 2020, 5, 11, 6021–6030

Publication Date (Web):March 13, 2020

https://doi.org/10.1021/acsomega.9b04398

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Abstract

Anacardic acid (AA) and its derivatives are well-known for their therapeutic applications ranging from antitumor, antibacterial, antioxidant, anticancer, and so forth. However, their poor pharmacokinetic and safety properties create significant hurdles in the formulation of the final drug molecule. As a part of our endeavor to enhance the potential and exploration of the anticancer activities, a detailed study on the properties of selected AA derivatives was performed in this work. A comprehensive analysis of the drug-like properties of 100 naturally occurring AA derivatives was performed, and the results were compared with certain marketed anticancer drugs. The work focused on the understanding of the interplay among eight physicochemical properties. The relationships between the physicochemical properties, absorption, distribution, metabolism, and excretion attributes, and the in silico toxicity profile for the set of AA derivatives were established. The ligand efficacy of the finally scrutinized 17 AA derivatives on the basis of pharmacokinetic properties and toxicity parameters was further subjected to dock against the potential anticancer target cyclin-dependent kinase 2 (PDB ID: 1W98). In the docked complex, the ligand molecules (AA derivatives) selectively bind with the target residues, and a high binding affinity of the ligand molecules was ensured by the full fitness score using the SwissDock Web server. The BOILED-Egg model shows that out of 17 scrutinized molecules, 3 molecules exhibit gastrointestinal absorption capability and 14 molecules exhibit permeability through the blood–brain barrier penetration. The analysis can also provide some useful insights to chemists to modify the existing natural scaffolds in designing new anacardic anticancer drugs. The increased probability of success may lead to the identification of drug-like candidates with favorable safety profiles after further clinical evaluation.

1. Introduction

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Cancer is one of the major concerns in the medical field as it causes increasing number of deaths day by day. (1) In the past decades, there have been numerous anticancer drugs synthesized. However, tumor recurrence and the adverse effects of the drugs because of toxic intolerance are the key problems in the treatment of cancer. Thus, there is an urgent and desperate need of finding anticancerous drug molecules with negligible side effects and high efficacy. The naturally occurring products have received special attention toward the preparation of novel cancer preventives and therapeutic agents. (2−4) Particularly, more natural products were identified with potential anticancer activity. (5,6) In the present work, virtual screening and suitability of anacardic acid (AA) derivatives that inhibit the anticancer target cyclin-dependent kinase 2 (PDB ID: 1W98) were studied. AA originates from the nutshells of Anacardium occidentale (cashew) (7) and found to act as an antitumor, antibiotic, antioxidant, and gastroprotective agent. (8) It is a combination of numerous closely related organic compounds, each consisting of salicylic acid substituted with an alkyl chain. In addition, it is used as a synthon for the production of a variety of biologically active compounds and a capping agent for the development of nanomaterials. (9) For the treatment of the most serious pathophysiological disorders like cancer, oxidative damage, inflammation, and obesity, AA and its derivatives have been strongly supported as therapeutic agents. (7) Recent studies show that AA derivatives exert their action in treating ovarian cancer, prostate cancer, breast carcinoma, and lung carcinoma through various mechanisms. (10−13) AA acts as a potential inhibitor of histone acetyltransferase activity and sensitizes tumor cells to ionizing radiation. (13) With the anticipation that AA can be eventually applied in the medicinal industry after successful preclinical trials, Xiu et al. have investigated the role of AA in cancer. (14)

However, during the clearance of the molecule under clinical trials, wastage of the drugs and human efforts is unavoidable. In this regard, computation methods were developed to predict the human pharmacokinetic properties. With different levels of complexity for the screening of large data set compounds, a variety of useful in silico ADME (absorption, distribution, metabolism, excretion) models have been established. Nowadays, the in silico tools are faster, simpler, and more cost-effective than transitional investigational procedures. (15) At present, because of the toxicity or lag of optimal pharmacokinetics properties, large attrition rates of preclinical and clinical candidates were observed in pharmaceutical industry. It is possible for medicinal chemists to control the pharmacokinetic and toxicity properties of a molecule through the structural modifications. (16) Hence, in the present work, physicochemical, ADME attributes and in silico toxicity (17) of 100 AA derivatives were evaluated, and the results were compared with well-known anticancer drugs. The study would definitely help to identify the suitable oral AA-based drug molecules based on the abovementioned properties and their binding activities with the target cyclin-dependent kinase 2. Figure 1 shows the schematic diagram of the work done in which the selection of compounds and screening methods were illustrated.

Figure 1. Flowchart illustrating the selection of AA derivatives, screening process, and their interactions with the target (PDB ID: 1W98).

2. Materials and Methods

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One of the main causes of drug development termination is poor pharmacokinetic properties. Less or no toxicity, good oral bioavailability, and optimum values of physicochemical properties are the key parameters for the discovery of anticancer drugs. In the present work, 100 AA derivatives were selected from the previous literatures (8−14,18,19) for the evaluation of their pharmacokinetic properties. Among these, the derivatives AA1–AA25 were obtained by alkyl chain modifications, whereas AA26–AA50 were obtained by modifying both the alkyl chain and functional groups (Figures S1 and S2). AA51–AA100 derivatives were obtained by introducing functional groups like hydroxyl (−OH) and carboxylic (−COOH) groups (Figures S3 and S4). A complete list of AA derivatives used in this study is depicted in Table S1, whereas the name and structures of the finally scrutinized molecules are depicted in Table 1 and the physicochemical properties of these derivatives are listed in Tables 2–

Table 1. Names and Structures of the Screened Out Derivatives

Table 2. Important Computed Physicochemical Properties of the Screened Out AA Derivatives^a

AA derivatives	MW	n_Rot	HBA	HBD	TPSA	M log P	Ali log S	MR
AA11	328.4	9	4	2	66.76	3.66	–6.79	95.4
AA12	302.32	7	5	2	75.99	2.41	–5.19	82.51
AA16	264.36	9	3	2	57.53	3.55	–6.62	78.85
AA20	274.27	4	5	4	97.99	1.91	–4.88	73.73
AA21	242.27	4	3	2	57.53	3.06	–4.76	69.68
AA22	290.27	4	6	5	118.22	1.37	–4.94	75.75
AA23	220.26	3	3	2	57.53	2.39	–5.01	62.31
AA24	238.28	7	4	3	77.76	1.93	–4.32	65.59
AA25	264.32	9	4	2	74.6	2.37	–5.12	74.24
AA33	266.33	9	4	2	66.76	2.45	–4.8	74.71
AA34	294.39	11	4	2	66.76	2.95	–5.92	84.33
AA72	426.59	5	3	1	34.15	4.21	–5.3	127.19
AA75	388.51	3	4	0	52.83	4.4	–5.08	109.46
AA95	262.34	1	3	0	35.53	3.16	–5.13	75.91
AA96	260.33	1	3	0	35.53	3.08	–4.83	76.23
AA97	276.33	1	4	0	48.06	2.31	–3.69	74.88
AA98	276.33	1	4	0	52.6	2.23	–3.54	76.11

^{^a}

Optimal range: molecular weight (MW) ≤ 600, lipophilicity log or Moriguchi octane–water partition coefficient (M log P) ≤ 5, aqueous solubility descriptor (Ali log S) ≤ 0, hydrogen-bonded acceptor (HBA) ≤ 10, hydrogen-bonded donor (HBD) ≤ 5, topological polar surface area (TPSA) ≤ 150 Å², number of rotatable bonds (n_Rot) ≤ 10, and molar refractivity (MR) ≤ 155.

Table 3. Important Computed ADMET Properties of the Screened Out AA Derivatives^a

AA derivatives	Caco2 permeability (log P_app in 10^–6 cm/s)	intestinal absorption (human) (% absorbed)	V_Dss (human) (log L/kg)	fraction unbound (human)	P-gp substrate (yes/no)
AA11	0.684	98.43	–1.596	0.04	no
AA12	1.07	100	–1.485	0.125	yes
AA16	1.25	95.899	–1.496	0.232	no
AA20	0.873	56.592	–0.398	0.199	yes
AA21	1.249	96.995	–1.12	0.089	yes
AA22	0.305	46.001	–0.308	0.153	yes
AA23	1.222	89.976	–0.231	0.206	no
AA24	0.888	95.688	–1.723	0.41	no
AA25	0.92	97.934	–1.641	0.29	no
AA33	1.127	91.257	–0.035	0.166	yes
AA34	1.084	90.567	0.014	0.113	yes
AA72	1.314	97.793	1.026	0.007	yes
AA75	1.568	100	–0.158	0	no
AA95	1.031	96.303	0.107	0.268	no
AA96	1.778	94.729	0.161	0.202	no
AA97	1.386	95.664	0.083	0.225	no
AA98	1.351	97.828	–0.082	0.249	no

^{^a}

Caco-2 cell permeability (log P_app in 10^–6 cm/s >0.09); intestinal absorption (human), % absorbed (>30); V_Dss (human) (log L/kg) (low if <−0.15 and high if >0.45).

Table 4. Important Computed Physicochemical Properties of Some Marketed Anticancer Drugs

Drugs	MW	n_Rot	HBA	HBD	TPSA	M log P	Ali log S	MR
Abemaciclib	502.63	7	7	1	75	2.87	–5.38	154.18
Ambochlorin	293.37	4	4	0	78.29	1.71	–3.3	83.81
Anastrozole	276.21	5	6	1	74.92	2.03	–4.6	64.19
Capecitabine	317.22	3	7	1	95.23	1.43	–3.63	77.26
Erivedge (Vismodegib)	421.3	5	4	1	84.51	3.24	–5.31	107
Flutamide	499.61	11	5	2	87.55	1.71	–5.25	150.43
Nelarabine	359.35	8	8	3	122.91	0.53	–2.71	85.25
Nilutamide	167.19	0	3	2	119.28	–0.96	–2.31	43.34
Osimertinib	297.27	3	8	4	148.77	–2.12	–1.61	69.17
Purinethol	304.21	9	2	1	40.54	3.29	–2.17	81.01

Table 5. Important Computed ADMET Properties for Some Marketed Anticancer Drugs

Drugs	Caco2 permeability (log P_app in 10^–6 cm/s)	intestinal absorption (human) (% absorbed)	V_Dss (human) (log L/kg)	fraction unbound (human)	P-gp substrate (yes/no)
Abemaciclib	1.38	88.951	0.535	0.285	yes
Ambochlorin	1.069	98.691	–0.03	0.138	no
Anastrazole	0.869	88.757	–0.118	0.029	yes
Capecitabine	1.2	87.504	–0.423	0.097	no
Erivedge (Vismodegib)	1.074	94.883	–0.075	0.127	no
Flutamide	0.811	95.992	1.093	0.145	yes
Nelarabine	0.319	51.344	–0.073	0.424	no
Nilutamide	1.207	84.051	–0.421	0.636	yes
Osimertinib	–0.023	48.895	–0.013	0.841	no
Purinethol	1.439	92.268	–0.165	0.117	no

Table 6. Computed Safety End Points for AA Derivatives

Der.	CYP2D6 inhibitor	CYP3A4 inhibitor	total clearance	renal OCT2 substrate	AMES toxicity	hERG I inhibitor	oral rat acute toxicity (LD₅₀)	oral rat chronic toxicity (LOAEL)	hepatotoxicity	skin sensitization
AA11	no	no	0.658	no	no	no	2.901	2.237	no	no
AA12	no	no	0.544	no	no	no	2.919	2.074	no	no
AA16	no	no	1.312	no	no	no	2.53	2.759	no	no
AA20	no	no	0.505	no	no	no	2.353	1.774	no	no
AA21	no	no	0.656	no	no	no	2.673	2.888	no	no
AA22	no	no	0.333	no	no	no	2.317	3.039	no	no
AA23	no	no	0.551	no	no	no	2.432	2.207	no	no
AA24	no	no	0.672	no	no	no	2.324	2.445	no	no
AA25	no	no	1.265	no	no	no	2.554	2.247	no	no
AA33	no	no	0.828	no	no	1.987	2.141	no	no	no
AA34	no	no	1.488	no	no	no	2.097	2.192	no	no
AA72	yes	no	0.725	yes	no	no	2.054	1.463	yes	no
AA75	no	no	0.67	no	no	no	1.829	2.357	yes	no
AA95	no	no	1.351	no	no	no	2.012	2.044	no	no
AA96	no	no	0.619	no	no	no	2.228	1.871	no	no
AA97	no	no	1.174	no	no	no	2.15	1.701	no	no
AA98	no	no	0.645	no	no	no	2.231	1.756	no	no

The ADME-related physicochemical properties of 100 AA derivatives including the marketed anticancer drugs were predicted by the Swiss ADME online Web server. (20) Two-dimensional structures were drawn with the help of Cambridge software, that is, ChemDraw Pro, version 12.0. A simplified molecular input line entry system of all AA derivatives was generated with the help of an online tool, that is, Swiss ADME. The physicochemical properties, lipophilicity and solubility, of the derivatives were considered for the analysis. (21)

In addition, the BOILED-Egg model of the molecules was predicted to reveal the capability of gastrointestinal (GI) absorption and permeability of the blood–brain penetration barrier. (22) The cutoff values of the physicochemical properties were set by certain rules, that is, Lipinski’s rule of five (ROF), bioavailability score, Ghose’s, and Veber’s rules. (23−25) For drug-likeliness, the molecular parameters such as MW (molecular weight), HBD (hydrogen bond donor), HBA (hydrogen bond acceptor), log P (lipophilicity log), log S (aqueous solubility), TPSA (topological polar surface area), MW, n_Rot (number of rotatable bonds), and MR (molar refractivity) were evaluated. For predicting the aforesaid properties, Swiss vector machine algorithm (26) is used.

There are two more important parameters, that is, plasma proteins (F_u) and volume of distribution (V_Dss), which help in the determination of the distribution of derivatives. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of all AA derivatives were analyzed through the online available tool pkSCM (http://bleoberis.bioc.cam.ac.uk/pkcsm/). (27)

In silico data corresponding to the major human cytochrome P450 (CYP) isoforms involved in drug metabolism, such as CYP2C9, CYP2D6, and CYP3A4, were also generated. To determine the excretion routes of AA derivatives, the total clearance and renal OCT2 substrate were predicted quantitatively. In drug attrition, the safety profile of the derivatives comes under major factors. (28) As per pharmacokinetic analysis, we assess some of the major toxicity end points of all derivatives. Moreover, certain safety parameters such as LD50, hepatotoxicity, skin sensitization, cellular toxicity, and hERG liability (inhibition of dofetilide binding) were also evaluated.

After the pharmacokinetic evaluation of all the AA derivatives, 17 AA molecules were chosen based on the cutoff values set by Lipinski’s ROF, bioavailability score, Ghose’s, and Veber’s rules. Finally, the chosen molecules were docked with cyclin-dependent kinase 2 to evaluate their binding affinities and active binding residues. For this process, the SwissDock docking server (http://www.swissdock.ch) is used. The preparation of the target for docking was done by UCSF chimera. Various docking parameters such as full fitness (FF, kcal/mol), total number of clusters, cluster rank, Gibbs free energy (ΔG), hydrogen bonding, deltaGligsolvpol, and so forth were analyzed.

3. Results and Discussion

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3.1. Structural and Physicochemical Properties

The main emphasis has been on defining the physicochemical property rules for the derivatives to reduce attrition and increase the likelihood of them at various stages of anticancer drug development. Based on the gold standards and earlier published research on various oral bioavailability rules, 100 AA derivatives were evaluated together with 10 marketed anticancer drugs against the key parameters of physicochemical properties, that is, lipophilicity, log P, MW, TPSA, HBD, HBA, n_Rot, and aqueous solubility (log S). (23−25) All physicochemical properties are depicted in Table S1.

The MW range of AA1–AA25 derivatives varies from 220 to 376, AA26–AA50 derivatives varies from 264 to 518, and AA51–AA80 derivatives varies from 388 to 598, whereas the MW range for AA81–AA100 is much broader and varies from 260 to 597. The M log P value of AA1–AA25 derivatives varies from 1.4 to 6, AA26–AA50 derivatives varies from 2.4 to 5.3, and AA51–AA80 derivatives varies from 3.1 to 7.5, whereas AA81–AA100 derivatives show values varying from 2.2 to 6.4. There were no significant differences in the log P values among the four groups, although the alkyl-modified derivative set AA1–AA25 had a lower span of log P values; meanwhile, each set shows predicted values of some derivatives which are higher than the cutoff value set by the Lipinski rule, RO5 ≤ 4.15. This reflects the fact that molecules with out-of-range values of log P are poorly soluble in fats, oil, lipids, and nonpolar solvents. The predicted polarity (TPSA) ranges from 56 to 157 Å² for AA1–AA25 derivatives, 20 to 120 Å² for AA26–AA50 derivatives, 14 to 77 Å² for AA51–AA80 derivatives, and 35 to 115 Å² for AA81–AA100 derivatives. According to the cutoff values set for TPSA (≤140 Å²) by Veber et al., (24) 95% of the AA derivatives reported in this study are likely to have high probability of oral bioavailability. A minimal number of HBDs ranging from 0 to 5 was found in the AA derivatives.

All the 100 derivatives of AA in this study satisfy the rule of Lipinski, HBA < 10. One important parameter for the oral bioavailability is “MR” described by the Ghose filter. (25) According to Lipinski’s rule, the value of MR should lie between 40 and 130 (23) for drug-likeness. The derivatives AA1–AA50 show that all the predicted values fall within the range as described by the Ghose filter rule, whereas the derivative set AA50–AA100 shows 30% violation.

In order to accurately access drug-likeness, Lipinski’s RO5, Ghose filter, Vebers’s, Egan’s, and Muegge’s rules are compared with certain marketed drugs. The detailed data set of all AA derivatives with the violation of rules is shown in Figure 2.

Figure 2. Results of AA derivatives against different violations.

The graph shown in Figure 2a reveals that most of the derivatives show one violation of each rule, and few structures viz. AA11, AA12, AA16, and AA20–AA25 did not show any violation. Hence, they can be provisionally approved for preclinical trials. The structures that show three violations of the Muegge and Ghose filters must be excluded from further preclinical processes. In Figure 2b, it is clear that the structures AA33 and AA34 did not show any violation, and most of the derivatives violate more than one rule for each filter. The Lipinski RO5 rule graph as shown in Figure 2c,d suggests that the compounds AA72, AA75, and AA95–AA98 can be subjected for further preclinical trials. Out of 100 investigated compounds, only 17 compounds fall within the allowed range of physicochemical properties and satisfy all the key parameters of physicochemical properties.

3.2. Comparison of Physicochemical Properties of AA Derivatives with Marketed Anticancer Drugs

Our analysis shows that the optimal property ranges (covering 100 AA derivatives) are 200 < MW ≤ 600, 1 < M log P ≤ 5, −6 ≤ Ali log S ≤ 0, 2 ≤ HBA ≤ 10, 1 ≤ HBD ≤ 5, 50 ≤ TPSA ≤ 150 Å², 0 ≤ n_Rot ≤ 10, and 40 ≤ MR ≤ 155. They may be very helpful in the prospective design of anticancer molecules. According to the RO5 rule, the key parameters of physicochemical properties showed better results as compared to the marketed anticancer drugs. The poor biopharmaceutical properties of the molecules, viz. poor aqueous solubility and slow dissolution rate resulted in poor oral bioavailability. In general, poor aqueous solubility is connected to high lipophilicity, and hydrophilic derivatives are connected to poor permeability, which means low absorption. Hence, ionization constants, solubility, and lipophilicity measurements are helpful in the high-throughput drug discovery paradigm. The relationship between lipophilicity and pharmacokinetic properties is explained in in silico studies. (29,30) In the present work, quantitative analysis shows that the finally scrutinized AA derivatives were predicted to have a higher optimum range of 13.18 for M log P, whereas the predicted values of M log P for the marketed anticancer drugs are in the range 2.12–5.6. Tables S1 and S2 depict the physicochemical and ADMET parameters of all the selected molecules.

3.3. BOILED-Egg for Prediction of GI Absorption and Brain Penetration

In the drug development process, GI absorption and blood–brain barrier (BBB) penetration play an important role. The BOILED-Egg model helps in the computation of polarity and lipophilicity of derivatives as it gives datasets with accuracy, speed, and clear graphical outputs. (22) This model helps in drug development by filtering the chemical libraries.

In the BOILED-Egg model, the high probability of passive absorption of the GI tract is represented by the white region, whereas the yellow region (yolk) represents the high probability of the BBB penetration. In addition, the blue color indicator of the molecule shows that the molecule is actively effluxed by P-glycoprotein, represented as (PGP⁺), whereas the red color indicator shows the nonsubstrate of P-gp, represented as (PGP^–).

The analysis predicts that the molecules AA1–AA25 (Figure S5a) show high GI absorption, with nearly 40% of the molecules also exhibiting BBB penetration, and all of them are predicted as the nonsubstrates of P-gp (PGP^–); 90% of the molecules AA26–AA50 (Figure S5b) show GI absorption, with nearly 40% of them also exhibiting BBB penetration. The BOILED-Egg plot of all the AA derivatives is presented in Figure S5. The predicted results of the derivatives AA51–AA80 (Figure S5c) consisting of benzamide and benzyl amine are shown. All the benzamide-based AA molecules and most of the benzyl amine-substituted AA derivatives show low GI absorption, and they do not exhibit significant BBB permeability. Most of the derivatives in the molecule set AA5–AA80 are P-gp substrates. The prediction of the BOILED-Egg results of the molecule set AA81–AA100 (Figure S5d), which includes thiazole, imidazole, oxazole, sildenafil, dihydropyridine, and macrolide AA derivatives, shows low GI absorption, and they do not exhibit BBB permeation. The BOILED-Egg model prediction of GI absorption and BBB permeation of the finally scrutinized 17 AA derivatives is presented in Figure 3.

Figure 3. BOILED-Egg model of AA derivatives.

3.4. Prediction of ADMET and Related Properties

For the development of a drug, the derivatives should have good ADMET profile. With the help of significant advancement in high-throughput in vitro ADME, computational scientists were able to predict the potential liabilities, that is, susceptibility to efflux transporters, low permeability, and so forth, of derivatives, which are associated with new potential derivatives. For the assessment of Caco2 cell permeability, P-gp efflux liability, and human intestinal absorption of anacardic derivatives, we have evaluated the ADME properties (in silico profiling). (31) On the basis of the ADME model, we can evaluate the permeability of a molecule, whether it is low or high. The permeability, that is, log P_app (10^–6 cm/s) rate, is considered to be high if log P_app > 0.9 and considered to be low if log P_app < 0.9. The Caco2 cell permeability of AA derivatives is mentioned in Table S2.

Of the AA derivatives, 80% show high log P_app values. Similar results were also analyzed in the assessment of P-gp efflux liabilities of AA derivatives. The assessment of P-gp efflux liabilities was done with the help of preADMET’s [https://preadmet.bmdrc.kr/] P-gp substrate model. Only 25% of anacardic derivatives were found as P-gp efflux substrates. The predicted ADMET parameters of AA derivatives are listed in Table S2. For the achievement of an optimal clinical drug/derivative, a derivative should have high log P_app and low P-gp efflux liability.

In addition, we have calculated the total human intestinal absorption percentage (%). For the GI tract dissolution and stability, a systematic oral dosage should have pH 1–2 in fasted state and 3–7 in fed state in stomach, including a neutral environment of small intestine, that is, pH 4.4–6.6. (31) The human intestinal absorption percentage (%) of the AA derivatives was analyzed with the help of an online server tool, pkCSM. (27) Except two AA molecules (AA99 and AA100), the rest of the other AA derivatives shows good human intestinal absorption. The predicted human intestinal absorption percentage (%) values for all the AA molecules are listed in Table S2.

In plasma, almost all drugs exist in equilibrium between the bound and unbound states with serum proteins at different affinities. Only an unbound drug can show interactions with anticipated molecular targets. (22) Therefore, the efficiency of a drug is affected by the binding efficacy of the drug with whole blood proteins. With the help of the predictive model of pkCSM, we have evaluated the fraction unbound (F_u) and steady-state volume of distribution (V_Dss) of 100 AA derivatives. V_Dss is a key parameter, which helps in suggestion for the total dose of a drug. The predicted values of F_u and V_Dss of all AA derivatives are listed in Table S2.

For drug designing and screening of new chemical drugs, pharmaceutical industries use in silico studies for early prediction. (32) For evaluating AA derivatives as anticancer drugs, we have evaluated the toxicity end points with the help of the pkCSM tool. The toxicity end points consist of the inhibition of cytochrome P450 (CYPs) monooxygenase enzymes. (33) AMES toxicity, LD50 (lethal rat acute toxicity), hepatotoxicity, skin sensitization, and inhibition of hERG potassium ion channel effects are determined for the evaluation of drug–drug interactions (DDIs). (34) The toxicity data sets of all AA derivatives are listed in Table S3. With the help of pkCSM, inhibitions of CYP2D6 and CYP3A4 were qualitatively predicted and the results are depicted in Table S3. Out of 100 AA derivatives, 80% AA derivatives were evaluated as noninhibitors of CYP3A4, and only two AA derivatives show inhibition against CYP2D6. After the evaluation of these parameters, drug excretion and drug metabolism were evaluated. With the prior knowledge of metabolic pathways of drugs, one can easily predict DDIs, pharmacokinetics, and toxicities. (35) Here, our primary concern is the inhibition of CYP3A4, which helps in finding out the correlation with increasing MW and log P. (36) Inhibition of CYP3A4 is related to issues with DDIs and clearance. The total clearance of 100 AA derivatives was measured, which is a combination of hepatic and renal clearance, and is listed in Table S3.

The major evaluation that emerged from these data was that the derivatives showing clog P < 3 and TPSA > 75 Å² were 2.5 times more nontoxic, whereas derivatives showing high lipophilicity (clog P > 3) and low polar surface area (TPSA < 75 Å²) are considered to be highly toxic in short-term animal studies. Hence, we have evaluated the lipophilicity of AA derivatives. Lipophilicity with small polar functionalities has high chances of becoming toxic. From the evaluation, it is revealed that toxicity occurs when log P > 3; on the other hand, the value of TPSA shows very little or no influence on the drug toxicity. Hence, it is clear that the early prediction of log P and TPSA is very helpful in the drug designing and development process in order to avoid wastage of chemicals.

Establishment of meaningful correlations between the physicochemical properties and ADMET properties of AA derivatives might be useful for future anticancer drug discovery. Based on our analysis, the results of AA derivatives show good and accepted prediction of physicochemical properties in comparison to Lipinski’s RO5, Ghose filter, Vebers’s, Egan’s, and Muegge’s rules for oral bioavailable drugs and in comparison with the physicochemical properties of marketed anticancer drugs. The correlation of the results of the accepted physicochemical properties with the predicted ADMET results shows that only seven AA derivatives, AA11, AA22, AA24, AA25, AA95, AA97, and AA98, fall within the accepted range of the parameters of ADMET. However, the docking studies of the finally scrutinized 17 derivatives were investigated, as they acquire adequate pharmacokinetic properties for oral bioavailability.

3.5. Molecular Docking Studies

Molecular docking studies were analyzed for exploring the interaction mechanism between the receptor sites and inhibitors. (37) In the field of drug discovery, the prediction of interactions between molecules and their targets has a great importance. One can easily find out the mechanisms of selectivity by the docking of molecules with protein targets. (38−40) In this work, the activities of anacardic derivatives were screened out against the target cyclin-dependent kinase 2 (PDB ID: 1w98). Cyclin-dependent kinase 2, also known as cell-division protein kinase 2, is an enzyme usually found in humans. It is encoded as CDK2 gene. It is necessary for cell cycle progression and mostly overexpressed in cancer cells. By using the SwissDock Web server (http://www.swissdock.ch), molecular docking of all the filtered 17 AA derivatives (AA11, AA12, AA16, AA20–AA25, AA33, AA34, AA72, AA75, AA95, AA96, AA97, and AA98) was performed against human cyclins or cell division protein kinase 2 (PDB ID: 1w98). (41) For the cell cycle, cyclins are essential proteins. Perturbation of the cyclin function can cause cancer formation. The structural factors and atomic coordinates of the protein cyclin were deposited. (42) The results pointed out that the filtered AA derivatives form conventional bonds with the receptor sites. Different parameters like FF (kcal/mol), ΔG (Gibb’s free energy), ligand solvation energy, hydrogen bonding (interactions), and so forth of docking were analyzed. On the basis of FF and cluster formation, all suitable binding modes were analyzed. (43) All the output clusters were ranked in accordance with hydrogen bonding (interactions) and the FF score. A cluster rank “0” is considered to be the best FF score. A molecule is said to have more favorable binding modes with a better fit if the FF score shows greater negative value. (44) The docked conformations having the lowest binding energy were selected for discussion. (45) However, for the most favorable interaction, if a molecule has a small docking score, then it is said to have a higher binding affinity of ligands for a particular receptor. (46) The FF score, binding affinity, and active residues of docked conformations are depicted in Table 7. Out of 17 docked complexes, the derivatives AA20, AA21, and AA22 show three hydrogen-bonding interactions with the target residues, whereas the derivative AA75 shows the maximum FF score (−3054.45) with one hydrogen-bonding interaction with LEU 2.418 Å. The docked conformations of 17 AA derivatives and the target (PDB ID: 1w98) are presented in Figure 4.

Figure 4. Docked ligands with target-1W98: (a) AA11, (b) AA12, (c) AA16, (d) AA20, (e) AA21, (f) AA22 (g) AA23, (h) AA24, (i) AA25 (j) AA33, (k) AA34, (l) AA72 (m) AA75, (n) AA95, (o) AA96, (p) AA97, and (q) AA98.

Table 7. Results of Docking of AA Derivatives with 1W98

Der. docked with 1W98	ΔG	deltaGligsolvpol	FF (kcal/mol)	energy	(protein···ligand) sites type/binding residue/H-bonding distance
AA11	–7.2239	–9.9810	–3029.41	7.2787	N–H···O/GLN174/2.345 Å
					O···H/LYS170/2.344 Å
AA12	–7.5062	–11.9606	–3014.64	21.7154	N–H···O/GLN174/2.359 Å
					O···H/LYS170/2.155 Å
AA16	–6.3474	–7.9222	–3040.32	–9.9220	O···H/LEU113/2.618 Å
					N–H···O/LEU113/2.256 Å
AA20	–6.8278	–16.5444	–3045.13	7.2032	O···H/LEU277/1.953 Å
					O···H/TYR112/2.301 Å
					O···H/GLU109/2.646 Å
AA21	–6.5128	–8.9698	–3018.17	16.201	O···H/LYS170/2.013 Å
					O···H/THR171/2.575 Å
					N–H···O/GLN174/2.523 Å
AA22	–7.8004	–19.1000	–3041.91	5.6960	O···H/LEU277/2.19 Å
					O···H/GLU109/2.508 Å
					O···H/GLU278/2.478 Å
AA23	–6.7354	–7.7501	–3035.65	–1.1662	O···H/THR171/2.481 Å
AA24	–6.3980	–10.9386	–3038.37	–3.4394	O···H/GLU109/2.562 Å
					O···H/GLU109/2.310 Å
AA25	–6.9110	–11.2838	–3049.17	–12.0395	O···H/LYS170/2.512 Å
					N–H···O/GLN174/2.393 Å
AA33	–7.1697	–6.6352	–3034.61	–4.6578	O···H/THR171/2.150 Å
AA34	–7.3850	–7.5994	–3031.71	–6.3850	O···H/LYS170/2.586 Å
AA72	–7.8560	–7.7790	–3020.07	–4.9699	O···H/THR202/2.302 Å
AA75	–7.5994	–7.5706	–3054.45	–28.0006	N–H···N/LEU113/2.418 Å
AA95	–6.2015	–4.3915	–3006.90	16.0120	N–H···O/ARG114/2.275 Å
AA96	–6.4796	–4.7592	–3008.22	15.3224	N–H···O/ASN74/2.606 Å
AA97	–6.4855	–6.0909	–2787.35	240.0530	N–H···O/LEU113/2.580 Å
AA98	–6.4602	–7.4286	–3010.43	11.7630	N–H···O/ARG114/2.472 Å

4. Conclusions

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For the drug designing and development process, the evaluation of pharmacokinetic and physicochemical properties is the primary task. In the present work, 100 AA derivatives were evaluated with the in silico screening procedure based on ADME parameters. The results show the optimal property range (covering 100 derivatives of AA) used to select oral bioavailable drugs. From the evaluation of in silico computational studies including ADME, the pkCSM data revealed that 80% of the selected AA derivatives in this work have shown high Caco2 permeability of log P_app <0.9 and 25% of the AA derivatives were found as P-gp efflux substrates with low-to-moderate clearance rates. The docking results of the finally scrutinized 17 derivatives which were allowed to dock with the anticancer target cyclin-dependent kinase 2 reveal that the AA derivatives are strongly bound with the targets and inhibit the target through hydrogen-bonding interactions. Better bioactivity score, drug adsorption ability, and drug-likeness of these derivatives pave a new research arena with vegetable feedstocks. Rege et al. have recently explored the dual functionality of certain AA derivatives for efficient paclitaxel delivery in breast cancer therapy. (47,48) The higher binding affinity results of the 17 AA derivatives with the anticancer target (PDB ID: 1W98) and their in silico pharmacokinetic studies would definitely provide motivation to biochemists for performing further wet lab and clinical evaluations.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b04398.

Chemical structures of alkyl chain-modified AA derivatives (labeled from 1 to 29); chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 30 to 49; chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 50 to 76; chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 77 to 100; BOILED-Egg model of AA1–AA100 derivatives; important computed physicochemical properties for AA1–AA100; important computed ADMET properties for AA1–AA100 derivatives; and computed safety end points for AA1–AA100 derivatives (PDF)

ao9b04398_si_001.pdf (933.12 kb)

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Author Information

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Corresponding Authors
- Fahmina Zafar - Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India; http://orcid.org/0000-0001-5454-3981; Email: [email protected]
- Anjali Gupta - Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India; Email: [email protected]
- Nahid Nishat - Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India; Email: [email protected]
Authors
- Karthick Thangavel - Department of Physics, School of Electrical and Electronics Engineering, SASTRA Deemed University, Thanjavur 613 401, Tamil Nadu, India
- Kavita Khatana - Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India
- Ali Alhaji Sani - Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India
- Anujit Ghosal - Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India; Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India; School of Life Sciences, Beijing Institute of Technology, Beijing 100811, China
- Poonam Tandon - Department of Physics, University of Lucknow, Lucknow 226007, India; http://orcid.org/0000-0002-8120-0498
Notes
The authors declare no competing financial interest.

Acknowledgments

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F.Z. acknowledges Department of Science and Technology, New Delhi, India, for the Women Scientist Scheme (WOS) for Research in Basic/Applied Sciences, Rf# SR/WOSA/CS-97/2016. The authors are thankful to the Head, Department of Chemistry, Jamia Millia Islamia (JMI), and Galgotias University, for providing facilities to carry out the work.

References

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Xiu, Yin-Ling; Zhao, Yang; Gou, Wen-Feng; Chen, Shuo; Takano, Yasuo; Zheng, Hua-Chuan

PLoS One (2014), 9 (6), e99361/1-e99361/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Background: Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. Certain antitumor activities of AA have been reported in a variety of cancers. However, the function of AA in ovarian cancer, to date, has remained unknown. Methods: Ovarian cancer cell lines were exposed to AA, after which cell proliferation, apoptosis, invasion and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of Phosphatidylinositol 3-kinase (PI3K), vascular endothelial growth factor (VEGF) and caspase 3. Results: Our results showed that AA promotes ovarian cancer cell proliferation, inhibits late apoptosis, and induces cell migration and invasion, as well as lamellipodia formation. AA exposure significantly up-regulated PI3K and VEGF mRNA and protein expression, while, in contrast, it down-regulated caspase 3 mRNA and protein expression in comparison to untreated control cells. Conclusion: Taken together, our results demonstrate for the first time that AA may potentiate the proliferation, invasion, metastasis and lamellipodia formation in ovarian cancer cell lines via PI3K, VEGF and caspase 3 pathways.

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Sung, B.; Pandey, M. K.; Ahn, K. S.; Yi, T.; Chaturvedi, M. M.; Liu, M.; Aggarwal, B. B. Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis. Blood 2008, 111, 4880– 4891, DOI: 10.1182/blood-2007-10-117994

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Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis

Sung, Bokyung; Pandey, Manoj K.; Ahn, Kwang Seok; Yi, Tingfang; Chaturvedi, Madan M.; Liu, Mingyao; Aggarwal, Bharat B.

Blood (2008), 111 (10), 4880-4891CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)

Anacardic acid (6-pentadecylsalicylic acid) is derived from traditional medicinal plants, such as cashew nuts, and has been linked to anticancer, anti-inflammatory, and radiosensitization activities through a mechanism that is not yet fully understood. Because of the role of nuclear factor-κB (NF-κB) activation in these cellular responses, we postulated that anacardic acid might interfere with this pathway. We found that this salicylic acid potentiated the apoptosis induced by cytokine and chemotherapeutic agents, which correlated with the down-regulation of various gene products that mediate proliferation (cyclin D1 and cyclooxygenase-2), survival (Bcl-2, Bcl-xL, cFLIP, cIAP-1, and survivin), invasion (matrix metalloproteinase-9 and intercellular adhesion mol.-1), and angiogenesis (vascular endothelial growth factor), all known to be regulated by the NF-κB. We found that anacardic acid inhibited both inducible and constitutive NF-κB activation; suppressed the activation of IκBα kinase that led to abrogation of phosphorylation and degrdn. of IκBα; inhibited acetylation and nuclear translocation of p65; and suppressed NF-κB-dependent reporter gene expression. Down-regulation of the p300 histone acetyltransferase gene by RNA interference abrogated the effect of anacardic acid on NF-κB suppression, suggesting the crit. role of this enzyme. Overall, our results demonstrate a novel role for anacardic acid in potentially preventing or treating cancer through modulation of NF-κB signaling pathway.

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Tan, J.; Chen, B.; He, L.; Tang, Y.; Jiang, Z.; Yin, G.; Wang, J.; Jiang, X. Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling. Chin. J. Cancer Res. 2012, 24, 275– 283, DOI: 10.1007/s11670-012-0264-y

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Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling

Tan, Jing; Chen, Binghai; He, Leye; Tang, Yuxin; Jiang, Zhiqiang; Yin, Guangmin; Wang, Jinrong; Jiang, Xianzhen

Chinese Journal of Cancer Research (2012), 24 (4), 275-283CODEN: CJCRFH; ISSN:1000-9604. (Chinese Anti-Cancer Association)

Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. It is widely regarded as a non-specific histone acetyltransferase inhibitor of p300. The effects and the mechanisms of AA in LNCaP cells (prostate cancer cells) remain unknown. To investigate the effect of AA on LNCaP cells, we had carried out several expts. and found that AA inhibits LNCaP cell proliferation, induces G1/S cell cycle arrest and apoptosis of LNCaP cell. The mechanisms via which AA acts on LNCaP cells may be due to the following aspects. First, AA can regulate p300 transcription and protein level except for its mechanisms regulating function of p300 through post-translational modification in LNCaP cells. Second, AA can activate p53 through increasing the phosphorylation of p53 on Ser15 in LNCaP cells. AA can selectively activate p21 (target genes of p53). Third, AA can down-regulates androgen receptor (AR) through suppressing p300. Our study suggests that AA has multiple anti-tumor activities in LNCaP cells and warrants further investigation.

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Sun, Y.; Jiang, X.; Chen, S.; Price, B. D. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett. 2006, 580, 4353– 4356, DOI: 10.1016/j.febslet.2006.06.092

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Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation

Sun, Yingli; Jiang, Xiaofeng; Chen, Shujuan; Price, Brendan D.

FEBS Letters (2006), 580 (18), 4353-4356CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)

Histone acetyltransferases (HATs) regulate transcription, chromatin structure and DNA repair. Here, we utilized a novel HAT inhibitor, anacardic acid, to examine the role of HATs in the DNA damage response. Anacardic acid inhibits the Tip60 HAT in vitro, and blocks the Tip60-dependent activation of the ATM and DNA-PKcs protein kinases by DNA damage in vivo. Further, anacardic acid sensitizes human tumor cells to the cytotoxic effects of ionizing radiation. These results demonstrate a central role for HATs such as Tip60 in regulating the DNA damage response. HAT inhibitors provide a novel therapeutic approach for increasing the sensitivity of tumors to radiation therapy.

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Xiu, Y.-L.; Zhao, Y.; Gou, W.-F.; Chen, S.; Takano, Y.; Zheng, H.-C. Anacardic acid enhances the proliferation of human ovarian cancer cells. PLoS One 2014, 9, e99361 DOI: 10.1371/journal.pone.0099361

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Anacardic acid enhances the proliferation of human ovarian cancer cells

Xiu, Yin-Ling; Zhao, Yang; Gou, Wen-Feng; Chen, Shuo; Takano, Yasuo; Zheng, Hua-Chuan

PLoS One (2014), 9 (6), e99361/1-e99361/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

Background: Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. Certain antitumor activities of AA have been reported in a variety of cancers. However, the function of AA in ovarian cancer, to date, has remained unknown. Methods: Ovarian cancer cell lines were exposed to AA, after which cell proliferation, apoptosis, invasion and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of Phosphatidylinositol 3-kinase (PI3K), vascular endothelial growth factor (VEGF) and caspase 3. Results: Our results showed that AA promotes ovarian cancer cell proliferation, inhibits late apoptosis, and induces cell migration and invasion, as well as lamellipodia formation. AA exposure significantly up-regulated PI3K and VEGF mRNA and protein expression, while, in contrast, it down-regulated caspase 3 mRNA and protein expression in comparison to untreated control cells. Conclusion: Taken together, our results demonstrate for the first time that AA may potentiate the proliferation, invasion, metastasis and lamellipodia formation in ovarian cancer cell lines via PI3K, VEGF and caspase 3 pathways.

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Moda, T. L.; Torres, L. G.; Carrara, A. E.; Andricopulo, A. D. PK/DB: Database for pharmacokinetic properties and predictive in silico ADME models. Bioinformatics 2008, 24, 2270– 2271, DOI: 10.1093/bioinformatics/btn415

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PK/DB: database for pharmacokinetic properties and predictive in silico ADME models

Moda, Tiago L.; Torres, Leonardo G.; Carrara, Alexandre E.; Andricopulo, Adriano D.

Bioinformatics (2008), 24 (19), 2270-2271CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)

The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metab., and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compds. which represent 2973 pharmacokinetic measurements, including 5 models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water soly.). Availability: http://www.pkdb.ifsc.usp.br.

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van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise?. Nat. Rev. Drug Discovery 2003, 2, 192– 204, DOI: 10.1038/nrd1032

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ADMET in silico modelling: Towards prediction paradise?

van de Waterbeemd, Han; Gifford, Eric

Nature Reviews Drug Discovery (2003), 2 (3), 192-204CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)

A review with refs. Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chem. and high-throughput screening have significantly increased the no. of compds. for which early data on absorption, distribution, metab., excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

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Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem. 2008, 51, 817– 834, DOI: 10.1021/jm701122q

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Generation of a Set of Simple, Interpretable ADMET Rules of Thumb

Gleeson, M. Paul

Journal of Medicinal Chemistry (2008), 51 (4), 817-834CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

A set of simple, consistent structure-property guides have been detd. from an anal. of a no. of key ADMET assays run within GSK: soly., permeability, bioavailability, vol. of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P 450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using mol. properties that chemists intuitively know how to alter in a mol., namely, mol. wt., logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing mol. wt., logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study reemphasizes the need to focus on a lower mol. wt. and logP area of physicochem. property space to obtain improved ADMET parameters.

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Green, I. R.; Tocoli, F. E.; Lee, S. H.; Nihei, K.-i.; Kubo, I. Design and evaluation of anacardic acid derivatives as anticavity agents. Eur. J. Med. Chem. 2008, 43, 1315– 1320, DOI: 10.1016/j.ejmech.2007.08.012

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Design and evaluation of anacardic acid derivatives as anticavity agents

Green, Ivan R.; Tocoli, Felismino E.; Lee, Sang Hwa; Nihei, Ken-ichi; Kubo, Isao

European Journal of Medicinal Chemistry (2008), 43 (6), 1315-1320CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

On the basis of antibacterial anacardic acids, 6-pentadecenylsalicylic acids, isolated from the cashew apple, Anacardium occidentale L. (Anacardiaceae), a series of 6-alk(en)ylsalicylic acids were synthesized and tested for their antibacterial activity against Streptococcus mutans ATCC 25175. Among them, 6-(4',8'-dimethylnonyl)salicylic acid (I) was found to exhibit the most potent antibacterial activity against this cariogenic bacterium with the min. inhibition concn. (MIC) of 0.78 μg/mL.

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Mamidyala, S. K.; Ramu, S.; Huang, J. X.; Robertson, A. A. B.; Cooper, M. A. Efficient synthesis of anacardic acid analogues and their antibacterial activities. Bioorg. Med. Chem. Lett. 2013, 23, 1667– 1670, DOI: 10.1016/j.bmcl.2013.01.074

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Efficient synthesis of anacardic acid analogues and their antibacterial activities

Mamidyala, Sreeman K.; Ramu, Soumya; Huang, Johnny X.; Robertson, Avril A. B.; Cooper, Matthew A.

Bioorganic & Medicinal Chemistry Letters (2013), 23 (6), 1667-1670CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

Anacardic acid derivs. exhibit a broad range of biol. activities. In this report, an efficient method for the synthesis of anacardic acid derivs. was explored, and a small set of salicylic acid variants synthesized retaining a const. hydrophobic element (a naphthyl tail). The naphthyl side chain was introduced via Wittig reaction and the aldehyde installed using directed ortho-metalation reaction of the substituted o-anisic acids. The failure of ortho-metalation using unprotected carboxylic acid group compelled us to use directed ortho-metalation in which a tertiary amide was used as a strong ortho-directing group. In the initial route, tertiary amide cleavage during final step was challenging, but cleaving the tertiary amide before Wittig reaction was beneficial. The Wittig reaction with protected carboxylic group (Me ester) resulted in side-products whereas using sodium salt resulted in higher yields. The novel compds. were screened for antibacterial activity and cytotoxicity. Although substitution on the salicylic head group enhanced antibacterial activities they also enhanced cytotoxicity.

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Zoete, V.; Daina, A.; Bovigny, C.; Michielin, O. SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening. J. Chem. Inf. Model. 2016, 56, 1399– 1404, DOI: 10.1021/acs.jcim.6b00174

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SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening

Zoete, Vincent; Daina, Antoine; Bovigny, Christophe; Michielin, Olivier

Journal of Chemical Information and Modeling (2016), 56 (8), 1399-1404CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

SwissSimilarity is a new web tool for rapid ligand-based virtual screening of small to unprecedented ultralarge libraries of small mols. Screenable compds. include drugs, bioactive and com. mols., as well as 205 million of virtual compds. readily synthesizable from com. available synthetic reagents. Predictions can be carried out on-the-fly using six different screening approaches, including 2D mol. fingerprints as well as superpositional and fast nonsuperpositional 3D similarity methodologies. SwissSimilarity is part of a large initiative of the SIB Swiss Institute of Bioinformatics to provide online tools for computer-aided drug design, such as SwissDock, SwissBioisostere or SwissTargetPrediction with which it can interoperate, and is linked to other well-established online tools and databases. User interface and backend have been designed for simplicity and ease of use, to provide proficient virtual screening capabilities to specialists and nonexperts in the field. SwissSimilarity is accessible free of charge or login at http://www.swisssimilarity.ch.

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Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717, DOI: 10.1038/srep42717

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SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

Daina Antoine; Michielin Olivier; Zoete Vincent; Michielin Olivier; Michielin Olivier

Scientific reports (2017), 7 (), 42717 ISSN:.

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

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Daina, A.; Zoete, V. A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem 2016, 11, 1117– 1121, DOI: 10.1002/cmdc.201600182

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A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

Daina, Antoine; Zoete, Vincent

ChemMedChem (2016), 11 (11), 1117-1121CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to est. at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL Estd. permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small mols. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochem. descriptors and straightforwardly translated into mol. design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chem. libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

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Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2012, 64, 4– 17, DOI: 10.1016/j.addr.2012.09.019

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Veber, D. F.; Johnson, S. R.; Cheng, H.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45, 2615– 2623, DOI: 10.1021/jm020017n

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Molecular Properties That Influence the Oral Bioavailability of Drug Candidates

Veber, Daniel F.; Johnson, Stephen R.; Cheng, Hung-Yuan; Smith, Brian R.; Ward, Keith W.; Kopple, Kenneth D.

Journal of Medicinal Chemistry (2002), 45 (12), 2615-2623CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

Oral bioavailability measurements in rats for over 1100 drug candidates studied at Smith-Kline Beecham Pharmaceuticals (now Glaxo Smith-Kline) have allowed us to analyze the relative importance of mol. properties considered to influence that drug property. Reduced mol. flexibility, as measured by the no. of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of mol. wt. That on av. both the no. of rotatable bonds and polar surface area or hydrogen bond count tend to increase with mol. wt. may in part explain the success of the mol. wt. parameter in predicting oral bioavailability. The commonly applied mol. wt. cutoff at 500 does not itself significantly sep. compds. with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compds. which meet only the 2 criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area ≤140 Å2 (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examd. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a neg. effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examd. here for the in vivo clearance rate in the rat.

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Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999, 1, 55– 68, DOI: 10.1021/cc9800071

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A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases

Ghose, Arup K.; Viswanadhan, Vellarkad N.; Wendoloski, John J.

Journal of Combinatorial Chemistry (1999), 1 (1), 55-68CODEN: JCCHFF; ISSN:1520-4766. (American Chemical Society)

The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of org. synthesis and biochem. screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compds. in the thousands. With automated synthesis, the no. of compds. to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chem. libraries are made wisely. The objective of this work is to provide both quant. and qual. characterization of known drugs which will help to generate "drug-like" libraries. In this work the authors analyzed the Comprehensive Medicinal Chem. (CMC) database and seven different subsets belonging to different classes of drug mols. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quant. characterization based on computed physicochem. property profiles such as log P, molar refractivity, mol. wt., and no. of atoms as well as a qual. characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compds.) of the calcd. log P is between -0.4 and 5.6, with an av. value of 2.52. For mol. wt., the qualifying range is between 160 and 480, with an av. value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an av. value of 97. For the total no. of atoms, the qualifying range is between 20 and 70, with an av. value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonarom. heterocyclic rings are twice as abundant as the arom. heterocycles. Tertiary aliph. amines, alc. OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochem. properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chem. library.

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Cortes, C.; Vapnik, V. Support-Vector Networks. Mach. Learn. 1995, 20, 273– 297, DOI: 10.1023/a:1022627411411

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Pires, D. E. V.; Blundell, T. L.; Ascher, D. B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015, 58, 4066– 4072, DOI: 10.1021/acs.jmedchem.5b00104

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pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures

Pires, Douglas E. V.; Blundell, Tom L.; Ascher, David B.

Journal of Medicinal Chemistry (2015), 58 (9), 4066-4072CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. The authors have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. PkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties.

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Pellicciari, A. Attrition in the Pharmaceutical Industry - Reasons, Implications, and Pathways Forward. Edited by Alexander Alex, C. John Harris, Dennis A. Smith. ChemMedChem 2017, 12, 1097– 1098, DOI: 10.1002/cmdc.201600621

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Attrition in the Pharmaceutical Industry - Reasons, Implications, and Pathways Forward. Edited by Alexander Alex, C. John Harris, Dennis A. Smith

Pellicciari, Roberto

ChemMedChem (2017), 12 (13), 1097-1098CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

There is no expanded citation for this reference.

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van deWaterbeemd, H.; Smith, D. A.; Jones, B. C. Lipophilicity in PK design: Methyl, ethyl, futile. J. Comput.-Aided Mol. Des. 2001, 15, 273– 286, DOI: 10.1023/a:1008192010023

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Pliška, V.; Testa, B.; Waterbeemd, H. V. Lipophilicity in Drug Action and Toxicology; VCH Verlagsgesellschaft mbH: Weinheim (Federal Republic of Germany), 1996.

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Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: Misconceptions in drug discovery. Nat. Rev. Drug Discovery 2010, 9, 929– 939, DOI: 10.1038/nrd3287

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The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Smith, Dennis A.; Di, Li; Kerns, Edward H.

Nature Reviews Drug Discovery (2010), 9 (12), 929-939CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)

A review. Data from in vitro plasma protein binding expts. that det. the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compds. for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is detd. by the free (unbound) drug concn. surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concn. So, decisions based on free drug fraction could result in the wrong compds. being advanced through drug discovery programs. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.

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Di, L.; Kerns, E. H. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization; Elsevier publisher, 2008.
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Khojasteh, S. C.; Wong, H.; Hop, C. E. C. A. Pharmacokinetics. Drug Metabolism and Pharmacokinetics Quick Guide; Springer, 2011; p 1.

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Li, A. P.; Jurima-Romet, M. Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: Evaluation of model drugs terfenadine and rifampin. Cell Biol. Toxicol. 1997, 13, 365– 374, DOI: 10.1023/A:1007451911843

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Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: evaluation of model drugs terfenadine and rifampin

Li, A. P.; Jurima-Romet, M.

Cell Biology and Toxicology (1997), 13 (4/5), 365-374CODEN: CBTOE2; ISSN:0742-2091. (Kluwer)

The utility of primary human hepatocytes in the evaluation of drug-drug interactions is being investigated in our labs. Our initial approach was to investigate whether drug-drug interactions obsd. in humans in vivo could be reproduced in vitro using human hepatocytes. Two model drugs were studied: terfenadine and rifampin, representing compds. subjected to drug-drug interactions via inhibitory and induction mechanisms, resp. Terfenadine was found to be metabolized by human hepatocytes to C-oxidn. and N-dealkylation products as obsd. in humans in vivo. Metab. by human hepatocytes was found to be inhibited by drugs which are known to be inhibitory in vivo. Ki values for the various inhibitors were derived from the in vitro metab. data, resulting in the following ranking of inhibitory potency: For the inhibition of C-oxidn., ketoconazole > itraconazole > cyclosporin ∼ troleandomycin > erythromycin > naringenin. For the inhibition of N-dealkylation, itraconazole ≥ ketoconazole > cyclosporin ≥ naringenin ≥ erythromycin ≥ troleandomycin. Rifampin induction of CYP3A, a known effect of rifampin in vivo, was also reproduced in primary human hepatocytes. Induction of CYP3A4, measured as testosterone 6β-hydroxylation, was found to be dose-dependent, treatment duration-dependent, and reversible. The induction effect of rifampin was obsd. in hepatocytes isolated from all 7 human donors studied, with ages ranging from 1.7 to 78 yr. To demonstrate that the rifampin-induction of testosterone 6β-hydroxylation could be generalized to other CYP3A4 substrates, we evaluated the metab. of another known substrate of CYP3A4, lidocaine. Dose-dependent induction of lidocaine metab. by rifampin is obsd. Our results suggest that primary human hepatocytes may be a useful exptl. system for preclin. evaluation of drug-drug interaction potential during drug development, and as a tool to evaluate the mechanism of clin. obsd. drug-drug interactions.

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Danielsson, B. R.; Lansdell, K.; Patmore, L.; Tomson, T. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res. 2003, 55, 147– 157, DOI: 10.1016/s0920-1211(03)00119-0

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Phenytoin and phenobarbital inhibit human HERG potassium channels

Danielsson, Bengt R.; Lansdell, Kate; Patmore, Leslie; Tomson, Torbjorn

Epilepsy Research (2003), 55 (1-2), 147-157CODEN: EPIRE8; ISSN:0920-1211. (Elsevier Science B.V.)

Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (IKr) channel can be proarrhythmic and their clin. use has been assocd. with sudden unexpected death (SUD). Since SUD is about 20 times more common among people with epilepsy than in the general population, and some data indicate that drug treatment may contribute, we tested the hypothesis that the classic antiepileptic drugs phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) have a potential to block IKr. The whole cell patch-clamp recording technique was used to study the effects on IKr channels expressed by the human ether-a-go-go related gene (HERG) stably expressed in Human Embryo Kidney (HEK) 293 cells. Tail currents, which are purely related to HERG, were blocked with an IC50 (the concn. when 50% inhibition was obtained compared to control values) of 240 μM for PHT and 3 mM for PB. A 20% inhibition of tail currents was obtained at CBZ concns. of 250 and 500 μM. Collective data show that drugs with the same margins (ratio HERG IC50/unbound therapeutic concn.), as PHT and PB, may have arrhythmogenic potential, esp. when used in predisposed patients and in the case of drug-drug interactions. SUD in epilepsy is generally a seizure-related phenomenon. However, our data suggest that PHT and PB may play a contributing role, perhaps by making some patients more vulnerable to the cardiovascular depression induced by seizures.

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Hosey, C. M.; Benet, L. Z. Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions. Mol. Pharm. 2015, 12, 1456– 1466, DOI: 10.1021/mp500783g

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Predicting the Extent of Metabolism Using in Vitro Permeability Rate Measurements and in Silico Permeability Rate Predictions

Hosey, Chelsea M.; Benet, Leslie Z.

Molecular Pharmaceutics (2015), 12 (5), 1456-1466CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)

The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metab. and soly. of a drug. However, defining the extent of metab. relies upon clin. data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, the authors aimed to det. if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metab., to det. a ref. compd. representing the permeability rate above which compds. would be expected to be extensively metabolized, and to predict the major route of elimination of compds. in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calcd. using ADMET Predictor or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compds. was analyzed with receiver operating characteristic curves. Compds. that yielded the highest sensitivity-specificity av. were selected as permeability rate ref. stds. The major route of elimination of poorly permeable drugs was predicted by the authors' previously published model, and the accuracies and predictive values were calcd. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metab. of compds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco-2 and MDCK, resp., while theophylline predicted greater than 80% of extensively and poorly metabolized drugs correctly in PAMPA. A two-tier approach predicting elimination route predicts 72±9%, 49±10%, and 66±7% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is predicted in silico and 74±7%, 85±2%, and 73±8% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is detd. in vitro.

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Czechtizky, C.; Hamley, P. Small Molecule Medicinal Chemistry: Strategies and Technologies; John Wiley & Sons, 2015.

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Singh, U.; Gangwal, R. P.; Dhoke, G. V.; Prajapati, R.; Damre, M.; Sangamwar, A. T. 3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors. Arabian J. Chem. 2017, 10, S617– S626, DOI: 10.1016/j.arabjc.2012.10.023

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3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors

Singh, Udghosh; Gangwal, Rahul Prakashchand; Dhoke, Gaurao V.; Prajapati, Rameshwar; Damre, Mangesh; Sangamwar, Abhay T.

Arabian Journal of Chemistry (2017), 10 (Suppl._1), S617-S626CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)

Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme, which plays a vital role in fatty acid metab. and obesity induced type 2 diabetes. Herein, we have performed 3D-QSAR and mol. docking anal. on a novel series of (4-piperidinyl)-piperazines to design potent ACC inhibitors. This study correlates the ACC inhibitory activities of 68 (4-piperidinyl)-piperazine derivs. with several stereo-chem. parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The CoMFA and CoMSIA models exhibited excellent r2ncv values of 0.974 and 0.985, and r2cv values of 0.671 and 0.693, resp. CoMFA predicted r2pred of 0.910 and CoMSIA predicted r2pred of 0.963 showed that the predicted values were in good agreement with exptl. values. Glide5.5 program was used to explore the binding mode of inhibitors inside the active site of ACC. We have accordingly designed novel ACC inhibitors by utilizing the LeapFrog and predicted with excellent inhibitory activity in the developed models.

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Bendaif, H.; Melhaoui, A.; Ramdani, M.; Elmsellem, H.; Douez, C.; El Ouadi, Y. Antibacterial activity and virtual screening by molecular docking of lycorine from Pancratium foetidum Pom (Moroccan endemic Amaryllidaceae). Microb. Pathog. 2018, 115, 138– 145, DOI: 10.1016/j.micpath.2017.12.037

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Antibacterial activity and virtual screening by molecular docking of lycorine from Pancratium foetidum Pom (Moroccan endemic Amaryllidaceae)

Bendaif, H.; Melhaoui, A.; Ramdani, M.; Elmsellem, H.; Douez, C.; El Ouadi, Y.

Microbial Pathogenesis (2018), 115 (), 138-145CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)

Lycorine is an alkaloid isolated from bulbs of Pancratium foetidum Pom Amaryllidaceae of the genus Lycoris. It has very strong pharmacodynamics properties and biol. effects, among others, antimalarial, antiviral, antitumor, and anti-inflammatory. Lycorine has been identified and characterized by thin layer chromatog., IR and NMR (1H and 13C NMR, COZY, HMBC, HSQC and NOESY). The antibacterial activity of lycorine has been evaluated. Lycorine has a moderate antibacterial activity on the majority of strains studied, nevertheless it is more effective than Streptomycin and Ampicillin against bacteria: P. aeruginosa, En. cloacae. To confirm these results, it is necessary to use qual. techniques and methods, etc... We performed a virtual docking ligand-lycorine protein screening study to predict and characterize their mode of interaction with the LpxC receptor. Docking results have shown that lycorine can interact with target amino residues studied by hydrogen and metal-ion bonds. In addn., the ADME-Tox profile study has shown that lycorine is all in agreement, either with Lipinski's critics or with the toxicity stds.

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Karthick, T.; Tandon, P. Computational approaches to find the active binding sites of biological targets against busulfan. J. Mol. Model. 2016, 22, 142, DOI: 10.1007/s00894-016-3015-z

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Computational approaches to find the active binding sites of biological targets against busulfan

Karthick T; Tandon Poonam

Journal of molecular modeling (2016), 22 (6), 142 ISSN:.

Determination of electrophilic and nucleophilic sites of a molecule is the primary task to find the active sites of the lead molecule. In the present study, the active sites of busulfan have been predicted by molecular electrostatic potential surface and Fukui function analysis with the help of dispersion corrected density functional theory. Similarly, the identification of active binding sites of the proteins against lead compound plays a vital role in the field of drug discovery. Rigid and flexible molecular docking approaches are used for this purpose. For rigid docking, Hex 8.0.0 software employing fast Fourier transform (FFT) algorithm has been used. The partial flexible blind docking simulations have been performed with AutoDock 4.2 software; where a Lamarckian genetic algorithm is employed. The results showed that the most electrophilic atoms of busulfan bind with the targets. It is clear from the docking studies that busulfan has inhibition capability toward the targets 12CA and 1BZM. Graphical Abstract Docking of ligand and protein.

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Shaikh, S.; Shastri, S. L.; Naik, N. S.; Kulkarni, R.; Madar, J. M.; Shastri, L. A.; Joshi, S. D.; Sunagar, V. Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies. ChemistrySelect 2019, 4, 105– 115, DOI: 10.1002/slct.201802395

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Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies

Shaikh, Farzanabi; Shastri, Samundeeswari L.; Naik, Nirmala S.; Kulkarni, Rashmi; Madar, Jyoti M.; Shastri, Lokesh A.; Joshi, Shrinivas D.; Sunagar, Vinay

ChemistrySelect (2019), 4 (1), 105-115CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)

A series of substituted coumarin-1,2,4-triazolidine-3-thiones such as I [R = 7-Me, 6-Cl, 7,8-di-Me, etc.] and phenyl-1,2,4-triazolidine-3-thiones such as II [R = 4-Me2N, 3-HO-4-MeO, 4-Br-2-HO, etc.] was synthesized and evaluated for their antitubercular and antimicrobial activities. Most of the compds. I and II showed promising antitubercular activity against Mycobacterium tuberculosis. The title compds. I and II exhibited excellent in vitro antibacterial and antifungal activities. Mol. docking study was performed for all the synthesized compds. I and II with E.coli as antibacterial and Mycobacterium tuberculosis DprE1 as antituberculosis.

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Sidhu, A.; Kukreja, S. Synthesis of novel fluorinated benzothiazol-2-yl-1,2,4-triazoles: Molecular docking, antifungal evaluation and in silico evaluation for SAR. Arabian J. Chem. 2019, 12, 2118, DOI: 10.1016/j.arabjc.2015.01.009

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Kareem, A.; Nami, S. A. A.; Khan, M. S.; Bhat, S. A.; Mirza, A. U.; Nishat, N. Self-assembled transition metal dithiocarbamates of pyridine-3-carboxamide: synthesis, spectral characterization, thermal and biological studies. New J. Chem. 2019, 43, 4413, DOI: 10.1039/c8nj03660h

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Self-assembled transition metal dithiocarbamates of pyridine-3-carboxamide: synthesis, spectral characterization, thermal and biological studies

Kareem, Abdul; Nami, Shahab A. A.; Khan, Mohd Shoeb; Bhat, Shahnawaz Ahmad; Mirza, Azar Ullah; Laxmi; Nishat, Nahid

New Journal of Chemistry (2019), 43 (11), 4413-4424CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)

A novel bidentate dithiocarbamate ligand (ndtc) derived from pyridine-3-carboxamide, (nicotinamide) by the insertion reaction of CS2 and its subsequent self-assembled 1st row transition metal complexes M(ndtc)2 [where M = Co(II), Ni(II), Cu(II), and Zn(II) ions] was synthesized and characterized using various spectral techniques. The facile reaction between the transition metal halide and ndtc in a 1 : 2 molar ratio yielded the aforesaid complexes in high yields. The formation of a single product was confirmed by thin layer chromatog. CHNS, IR, NMR spectra (1H and 13C), TGA/DTA, XRD, UV-visible spectra, magnetic moment, and cond. measurements were performed to ascertain the proposed structure of the synthesized complexes. From the abovementioned studies, the complexes possess an octahedral arrangement, except for the Cu(II) ion, which has a square-planar structure. The dithiocarbamate moiety was found to coordinate in a bidentate sym. fashion with the metal ions in all the complexes. The complexes were screened against a variety of human cancer cell lines such as human hepatocellular carcinoma (Hep3B), human breast adenocarcinoma (MCF7), and normal cells (PBMC). The complexes displayed moderate to good cytotoxicity on these cancer cell lines. However, Cu(ndtc)2 is most potent on MCF7, with an IC50 value, 3.56 ± 1.1500, while Zn(ndtc)2 was the most potent against liver and cervical cancer cell lines, with IC50 values, 2.32 ± 1.5000 and 3.58 ± 1.6100 in micro-molar concns., resp. The antioxidant potential of the ndtc and its metal complexes was detd. using DPPH, and Cu(ndtc)2 is most efficient. Also, mol. docking simulations were also performed for the ndtc and its complexes, which confirmed the findings of the cytotoxicity.

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Kaviyarasi, N. S.; Prashantha, C. N.; Suryanarayana, V. V. S. In Silico Analysis of Inhibitor and Substrate Binding Site of Serrapeptidase from Serratia Marcescens MTCC 8708. Int. J. Pharmacol. Pharm. Sci. 2016, 8, 123– 128
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In silico analysis of inhibitor and substrate binding site of serrapeptidase from Serratia marcescens MTCC 8708

Kaviyarasi, N. S.; Prashantha, C. N.; Suryanarayana, V. V. S.

International Journal of Pharmacy and Pharmaceutical Sciences (2016), 8 (4), 123-128CODEN: IJPPKB; ISSN:0975-1491. (Innovare Academic Sciences Pvt. Ltd.)

Objective: Serrapeptidase is a therapeutic enzyme broadly used as an anti-inflammatory drug to treat inflammatory diseases like arthritis, bronchitis, fibrocystic breast disease and sinusitis. The objective of present study is in silco analyzes of the substrate and inhibitor binding sites of serratiopeptidase, expressed from a cloned gene. Methods: The gene encoding Serrapeptidase was amplified from genomic DNA of Serratia marcescens MTCC 8707, an isolated from the flowers of summer squash plants. The gene was sequenced, the nucleotide sequence of 1464 nucleotides was submitted to Gen Bank nucleotide database and accession no. GI: KP869847 obtained. The develop amino acid sequence was used to predict 3D structure using different bioinformatics tools and software's Further, CABS-dock and Swiss Dock, the docking servers were used for enzyme-substrate/inhibitor binding site anal. The inflammatory mediators, bradykinin, and substance-P were used as substrates, whereas, EDTA and Lisinopril were used as an inhibitor for serrapeptidase. UCSF Chimera program was used for interactive visualization and anal. of docked results. Results: The docking studies show substrates bradykinin and substance-P bind near zinc binding site with min. RMSD value and the inhibitors EDTA and lisinopril showed favorable interaction at zinc binding site of serrapeptidase with min. free energy. Conclusion: The result of docking studies confirm that the substrate or inhibitor binds near zinc binding domain (HEXXH.) and the peptide bond of the substrate can be effectively cleaved by serrapeptidase.

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De Vita, D.; Pandolfi, F.; Ornano, L.; Feroci, M.; Chiarotto, I.; Sileno, I.; Pepi, F.; Costi, R.; Di Santo, R.; Scipione, L. New N,N-Dimethylcarbamate Inhibitors of Acetylcholinesterase: Design Synthesis and Biological Evaluation. J. Enzyme Inhib. Med. Chem. 2016, 31, 106– 113, DOI: 10.1080/14756366.2016.1220377

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New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

De Vita, Daniela; Pandolfi, Fabiana; Ornano, Luigi; Feroci, Marta; Chiarotto, Isabella; Sileno, Ilaria; Pepi, Federico; Costi, Roberta; Di Santo, Roberto; Scipione, Luigi

Journal of Enzyme Inhibition and Medicinal Chemistry (2016), 31 (sup4), 106-113CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)

A series of N,N-dimethylcarbamates contg. a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compds. 4 and 8, showed 85 and 69% of inhibition at 50 μM, resp. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aroms. rings of the dibenzylamino group reduce the inhibitory power. Compd. 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compd. 4 and by MALDI-TOF MS anal. of trypsinized AChE inhibited by compd. 4. Instead, compd. 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.

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Iftikhar, H.; Batool, S.; Deep, A.; Narasimhan, B.; Sharma, P. C.; Malhotra, M. In Silico Analysis of the Inhibitory Activities of GABA Derivatives on 4-Aminobutyrate Transaminase. Arabian J. Chem. 2017, 10, S1267– S1275, DOI: 10.1016/j.arabjc.2013.03.007

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In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase

Iftikhar, Hira; Batool, Sidra; Deep, Aakash; Narasimhan, Balasubramanian; Sharma, Prabodh Chander; Malhotra, Manav

Arabian Journal of Chemistry (2017), 10 (Suppl._1), S1267-S1275CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)

Reduced levels of γ-aminobutyric acid (GABA) are cause of quite a many diseases, and it cannot be directly introduced into the body to enhance its level because of the blood-brain barrier. Thus the technique used for the purpose involves the inhibition of aminobutyrate transaminase (ABAT), the enzyme catalyzing its degrdn. The structure of human ABAT is not currently known exptl., thus, it was predicted by homol. modeling using pig ABAT as template due to high level of sequence similarity and conservation. A series of new γ-aminobutyric acid (GABA) derivs. obtained from 4-(1,3-dioxoisoindolin-2-yl)butanoic acid are used in this study. These γ -aminobutyric acid (GABA) derivs. were used as ligand dockings against human ABAT as well as pig ABAT receptors.

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Chhajed, S. S.; Upasani, C. D. Synthesis, Biological Screening and Molecular Modeling Studies of Novel 3-Chloro-4-Substituted-1-(2-(1H-Benzimidazol-2-Yl)Phenyl))-Azetidin-2-Ones. J. Enzyme Inhib. Med. Chem. 2012, 27, 504, DOI: 10.3109/14756366.2011.598867

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Synthesis, biological screening and molecular modeling studies of novel 3-chloro-4-substituted-1-(2-(1H-benzimidazol-2-yl)phenyl)-azetidin-2-ones

Chhajed, Santosh S.; Upasani, Chandrashekhar D.

Journal of Enzyme Inhibition and Medicinal Chemistry (2012), 27 (4), 504-508CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)

In the present investigation synthesis of some novel 1-(2-(1H-benzimidazol-2-yl)phenyl)-3-chloro-4-(Un/substituted phenyl)azetidin-2-one antibacterial are reported. Structures of synthesized compds. were confirmed by spectral techniques (IR, Mass, 1H-NMR) All reactions were monitored with anal. thin layer chromatog. Synthesized compds. were docked in to the active site of enzyme transpeptidase. Four compds. were found to have good affinity for transpeptidase with potent antibacterial activity. A good correlation is found between in silico docking anal. and in vitro antibacterial activity.

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Rege, M. D.; Ghadi, R.; Katiyar, S. S.; Kushwah, V.; Jain, S. Exploring an interesting dual functionality of anacardic acid for efficient paclitaxel delivery in breast cancer therapy. Nanomedicine 2019, 14, 57, DOI: 10.2217/nnm-2018-0138

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Exploring an interesting dual functionality of anacardic acid for efficient paclitaxel delivery in breast cancer therapy

Rege, Madhura D.; Ghadi, Rohan; Katiyar, Sameer S.; Kushwah, Varun; Jain, Sanyog

Nanomedicine (London, United Kingdom) (2019), 14 (1), 57-75CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)

To explore the potential of paclitaxel (PTX)-loaded anacardic acid conjugated hydrophobized gelatin nanoparticles. Nanoparticles prepd. by nanopptn. technique were evaluated for various quality attributes (particle size, % entrapment efficiency) in vitro drug release, MCF-7 cell uptake, cell cytotoxicity, in vivo pharmacokinetics, antitumor efficacy and toxicity. The nanoparticles (250-300 nm, 74% entrapment efficiency) showed approx. 2.26-fold higher apoptosis index and approx. 5.86-fold redn. in IC50 value compared with PTX in MCF-7 cells. Also, approx. 3.51- and 1.36-fold increase in area under the curve compared with Intaxel and Nanoxel (both from Fresenius Kabi, Gurugram, India) was achieved. Significant tumor burden redn. (∼60%) and reduced toxicity was obsd. compared with marketed formulations. The hydrophobized gelatin nanoparticles displayed promising therapeutic potential, paving a new path for efficient PTX delivery.

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Figure 1

Figure 1. Flowchart illustrating the selection of AA derivatives, screening process, and their interactions with the target (PDB ID: 1W98).

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Figure 2

Figure 2. Results of AA derivatives against different violations.

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Figure 3

Figure 3. BOILED-Egg model of AA derivatives.

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Figure 4

Figure 4. Docked ligands with target-1W98: (a) AA11, (b) AA12, (c) AA16, (d) AA20, (e) AA21, (f) AA22 (g) AA23, (h) AA24, (i) AA25 (j) AA33, (k) AA34, (l) AA72 (m) AA75, (n) AA95, (o) AA96, (p) AA97, and (q) AA98.

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  Newman, David J.; Cragg, Gordon M.
  
  Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
  
  This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
  
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8. 8
  Hemshekhar, M.; Santhosh, M. S.; Kemparaju, K.; Girish, K. S. Emerging roles of anacardic acid and its derivatives: A pharmacological overview. Basic Clin. Pharmacol. Toxicol. 2012, 110, 122– 132, DOI: 10.1111/j.1742-7843.2011.00833.x
  
  8
  Emerging roles of anacardic acid and its derivatives: a pharmacological overview
  
  Hemshekhar, Mahadevappa; Santhosh, Martin Sebastin; Kemparaju, Kempaiah; Girish, Kesturu S.
  
  Basic & Clinical Pharmacology & Toxicology (2012), 110 (2), 122-132CODEN: BCPTBO; ISSN:1742-7835. (Wiley-Blackwell)
  
  A review. Anacardic acid (AA) is a bioactive phytochem. found in nutshell of Anacardium occidentale. Chem., it is a mixt. of several closely related org. compds., each consisting of salicylic acid substituted with an alkyl chain. The traditional Ayurveda depicts nutshell oil as a medicinal remedy for alexeritic, amebicidal, gingivitis, malaria and syphilitic ulcers. However, the enduring research and emerging evidence suggests that AA could be a potent target mol. with bactericide, fungicide, insecticide, anti-termite and molluscicide properties and as a therapeutic agent in the treatment of the most serious pathophysiol. disorders like cancer, oxidative damage, inflammation and obesity. Furthermore, AA was found to be a common inhibitor of several clin. targeted enzymes such as NFκB kinase, histone acetyltransferase (HATs), lipoxygenase (LOX-1), xanthine oxidase, tyrosinase and ureases. In view of this, we have made an effort to summarize the ongoing research on the therapeutical role of AA and its derivs. The current MiniReview sheds light on the pharmacol. applications, toxicity and allergic responses assocd. with AA and its derivs. Although the available records are promising, much more detailed investigations into the therapeutical properties, particularly the anti-cancer and anti-inflammatory activities, are urgently needed. We hope the present MiniReview will attract and encourage further research on elucidating and appreciating the possible curative properties of AA and its derivs. in the management of multifactorial diseases.
  
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9. 9
  Hamad, F.; Mubofu, E. Potential biological applications of bio-based anacardic acids and their derivatives. Int. J. Mol. Sci. 2015, 16, 8569– 8590, DOI: 10.3390/ijms16048569
  
  9
  Potential biological applications of bio-based anacardic acids and their derivatives
  
  Hamad, Fatma B.; Mubofu, Egid B.
  
  International Journal of Molecular Sciences (2015), 16 (4), 8569-8590CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
  
  Cashew nut shells (CNS), which are agro wastes from cashew nut processing factories, have proven to be among the most versatile bio-based renewable materials in the search for functional materials and chems. from renewable resources. CNS are produced in the cashew nut processing process as waste, but they contain cashew nut shell liq. (CNSL) up to about 30-35 wt. % of the nut shell wt. depending on the method of extn. CNSL is a mixt. of anacardic acid, cardanol, cardol, and Me cardol, and the structures of these phenols offer opportunities for the development of diverse products. For anacardic acid, the combination of phenolic, carboxylic, and a 15-carbon alkyl side chain functional group makes it attractive in biol. applications or as a synthon for the synthesis of a multitude of bioactive compds. Anacardic acid, which is about 65% of a CNSL mixt., can be extd. from the agro waste. This shows that CNS waste can be used to ext. useful chems. and thus provide alternative green sources of chems., apart from relying only on the otherwise declining petroleum based sources. This paper reviews the potential of anacardic acids and their semi-synthetic derivs. for antibacterial, antitumor, and antioxidant activities. The review focuses on natural anacardic acids from CNS and other plants and their semi-synthetic derivs. as possible lead compds. in medicine. In addn., the use of anacardic acid as a starting material for the synthesis of various biol. active compds. and complexes is reported.
  
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10. 10
  Xiu, Y.-L.; Zhao, Y.; Gou, W.-F.; Chen, S.; Takano, Y.; Zheng, H.-C. Anacardic acid enhances the proliferation of human ovarian cancer cells. PLoS One 2014, 9, e99361 DOI: 10.1371/journal.pone.0099361
  
  10
  Anacardic acid enhances the proliferation of human ovarian cancer cells
  
  Xiu, Yin-Ling; Zhao, Yang; Gou, Wen-Feng; Chen, Shuo; Takano, Yasuo; Zheng, Hua-Chuan
  
  PLoS One (2014), 9 (6), e99361/1-e99361/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Background: Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. Certain antitumor activities of AA have been reported in a variety of cancers. However, the function of AA in ovarian cancer, to date, has remained unknown. Methods: Ovarian cancer cell lines were exposed to AA, after which cell proliferation, apoptosis, invasion and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of Phosphatidylinositol 3-kinase (PI3K), vascular endothelial growth factor (VEGF) and caspase 3. Results: Our results showed that AA promotes ovarian cancer cell proliferation, inhibits late apoptosis, and induces cell migration and invasion, as well as lamellipodia formation. AA exposure significantly up-regulated PI3K and VEGF mRNA and protein expression, while, in contrast, it down-regulated caspase 3 mRNA and protein expression in comparison to untreated control cells. Conclusion: Taken together, our results demonstrate for the first time that AA may potentiate the proliferation, invasion, metastasis and lamellipodia formation in ovarian cancer cell lines via PI3K, VEGF and caspase 3 pathways.
  
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11. 11
  Sung, B.; Pandey, M. K.; Ahn, K. S.; Yi, T.; Chaturvedi, M. M.; Liu, M.; Aggarwal, B. B. Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis. Blood 2008, 111, 4880– 4891, DOI: 10.1182/blood-2007-10-117994
  
  11
  Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis
  
  Sung, Bokyung; Pandey, Manoj K.; Ahn, Kwang Seok; Yi, Tingfang; Chaturvedi, Madan M.; Liu, Mingyao; Aggarwal, Bharat B.
  
  Blood (2008), 111 (10), 4880-4891CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
  
  Anacardic acid (6-pentadecylsalicylic acid) is derived from traditional medicinal plants, such as cashew nuts, and has been linked to anticancer, anti-inflammatory, and radiosensitization activities through a mechanism that is not yet fully understood. Because of the role of nuclear factor-κB (NF-κB) activation in these cellular responses, we postulated that anacardic acid might interfere with this pathway. We found that this salicylic acid potentiated the apoptosis induced by cytokine and chemotherapeutic agents, which correlated with the down-regulation of various gene products that mediate proliferation (cyclin D1 and cyclooxygenase-2), survival (Bcl-2, Bcl-xL, cFLIP, cIAP-1, and survivin), invasion (matrix metalloproteinase-9 and intercellular adhesion mol.-1), and angiogenesis (vascular endothelial growth factor), all known to be regulated by the NF-κB. We found that anacardic acid inhibited both inducible and constitutive NF-κB activation; suppressed the activation of IκBα kinase that led to abrogation of phosphorylation and degrdn. of IκBα; inhibited acetylation and nuclear translocation of p65; and suppressed NF-κB-dependent reporter gene expression. Down-regulation of the p300 histone acetyltransferase gene by RNA interference abrogated the effect of anacardic acid on NF-κB suppression, suggesting the crit. role of this enzyme. Overall, our results demonstrate a novel role for anacardic acid in potentially preventing or treating cancer through modulation of NF-κB signaling pathway.
  
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12. 12
  Tan, J.; Chen, B.; He, L.; Tang, Y.; Jiang, Z.; Yin, G.; Wang, J.; Jiang, X. Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling. Chin. J. Cancer Res. 2012, 24, 275– 283, DOI: 10.1007/s11670-012-0264-y
  
  12
  Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling
  
  Tan, Jing; Chen, Binghai; He, Leye; Tang, Yuxin; Jiang, Zhiqiang; Yin, Guangmin; Wang, Jinrong; Jiang, Xianzhen
  
  Chinese Journal of Cancer Research (2012), 24 (4), 275-283CODEN: CJCRFH; ISSN:1000-9604. (Chinese Anti-Cancer Association)
  
  Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. It is widely regarded as a non-specific histone acetyltransferase inhibitor of p300. The effects and the mechanisms of AA in LNCaP cells (prostate cancer cells) remain unknown. To investigate the effect of AA on LNCaP cells, we had carried out several expts. and found that AA inhibits LNCaP cell proliferation, induces G1/S cell cycle arrest and apoptosis of LNCaP cell. The mechanisms via which AA acts on LNCaP cells may be due to the following aspects. First, AA can regulate p300 transcription and protein level except for its mechanisms regulating function of p300 through post-translational modification in LNCaP cells. Second, AA can activate p53 through increasing the phosphorylation of p53 on Ser15 in LNCaP cells. AA can selectively activate p21 (target genes of p53). Third, AA can down-regulates androgen receptor (AR) through suppressing p300. Our study suggests that AA has multiple anti-tumor activities in LNCaP cells and warrants further investigation.
  
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13. 13
  Sun, Y.; Jiang, X.; Chen, S.; Price, B. D. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett. 2006, 580, 4353– 4356, DOI: 10.1016/j.febslet.2006.06.092
  
  13
  Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation
  
  Sun, Yingli; Jiang, Xiaofeng; Chen, Shujuan; Price, Brendan D.
  
  FEBS Letters (2006), 580 (18), 4353-4356CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)
  
  Histone acetyltransferases (HATs) regulate transcription, chromatin structure and DNA repair. Here, we utilized a novel HAT inhibitor, anacardic acid, to examine the role of HATs in the DNA damage response. Anacardic acid inhibits the Tip60 HAT in vitro, and blocks the Tip60-dependent activation of the ATM and DNA-PKcs protein kinases by DNA damage in vivo. Further, anacardic acid sensitizes human tumor cells to the cytotoxic effects of ionizing radiation. These results demonstrate a central role for HATs such as Tip60 in regulating the DNA damage response. HAT inhibitors provide a novel therapeutic approach for increasing the sensitivity of tumors to radiation therapy.
  
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14. 14
  Xiu, Y.-L.; Zhao, Y.; Gou, W.-F.; Chen, S.; Takano, Y.; Zheng, H.-C. Anacardic acid enhances the proliferation of human ovarian cancer cells. PLoS One 2014, 9, e99361 DOI: 10.1371/journal.pone.0099361
  
  14
  Anacardic acid enhances the proliferation of human ovarian cancer cells
  
  Xiu, Yin-Ling; Zhao, Yang; Gou, Wen-Feng; Chen, Shuo; Takano, Yasuo; Zheng, Hua-Chuan
  
  PLoS One (2014), 9 (6), e99361/1-e99361/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  
  Background: Anacardic acid (AA) is a mixt. of 2-hydroxy-6-alkylbenzoic acid homologs. Certain antitumor activities of AA have been reported in a variety of cancers. However, the function of AA in ovarian cancer, to date, has remained unknown. Methods: Ovarian cancer cell lines were exposed to AA, after which cell proliferation, apoptosis, invasion and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of Phosphatidylinositol 3-kinase (PI3K), vascular endothelial growth factor (VEGF) and caspase 3. Results: Our results showed that AA promotes ovarian cancer cell proliferation, inhibits late apoptosis, and induces cell migration and invasion, as well as lamellipodia formation. AA exposure significantly up-regulated PI3K and VEGF mRNA and protein expression, while, in contrast, it down-regulated caspase 3 mRNA and protein expression in comparison to untreated control cells. Conclusion: Taken together, our results demonstrate for the first time that AA may potentiate the proliferation, invasion, metastasis and lamellipodia formation in ovarian cancer cell lines via PI3K, VEGF and caspase 3 pathways.
  
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15. 15
  Moda, T. L.; Torres, L. G.; Carrara, A. E.; Andricopulo, A. D. PK/DB: Database for pharmacokinetic properties and predictive in silico ADME models. Bioinformatics 2008, 24, 2270– 2271, DOI: 10.1093/bioinformatics/btn415
  
  15
  PK/DB: database for pharmacokinetic properties and predictive in silico ADME models
  
  Moda, Tiago L.; Torres, Leonardo G.; Carrara, Alexandre E.; Andricopulo, Adriano D.
  
  Bioinformatics (2008), 24 (19), 2270-2271CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
  
  The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metab., and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compds. which represent 2973 pharmacokinetic measurements, including 5 models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water soly.). Availability: http://www.pkdb.ifsc.usp.br.
  
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16. 16
  van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise?. Nat. Rev. Drug Discovery 2003, 2, 192– 204, DOI: 10.1038/nrd1032
  
  16
  ADMET in silico modelling: Towards prediction paradise?
  
  van de Waterbeemd, Han; Gifford, Eric
  
  Nature Reviews Drug Discovery (2003), 2 (3), 192-204CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  
  A review with refs. Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chem. and high-throughput screening have significantly increased the no. of compds. for which early data on absorption, distribution, metab., excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.
  
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17. 17
  Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem. 2008, 51, 817– 834, DOI: 10.1021/jm701122q
  
  17
  Generation of a Set of Simple, Interpretable ADMET Rules of Thumb
  
  Gleeson, M. Paul
  
  Journal of Medicinal Chemistry (2008), 51 (4), 817-834CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  
  A set of simple, consistent structure-property guides have been detd. from an anal. of a no. of key ADMET assays run within GSK: soly., permeability, bioavailability, vol. of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P 450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using mol. properties that chemists intuitively know how to alter in a mol., namely, mol. wt., logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing mol. wt., logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study reemphasizes the need to focus on a lower mol. wt. and logP area of physicochem. property space to obtain improved ADMET parameters.
  
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18. 18
  Green, I. R.; Tocoli, F. E.; Lee, S. H.; Nihei, K.-i.; Kubo, I. Design and evaluation of anacardic acid derivatives as anticavity agents. Eur. J. Med. Chem. 2008, 43, 1315– 1320, DOI: 10.1016/j.ejmech.2007.08.012
  
  18
  Design and evaluation of anacardic acid derivatives as anticavity agents
  
  Green, Ivan R.; Tocoli, Felismino E.; Lee, Sang Hwa; Nihei, Ken-ichi; Kubo, Isao
  
  European Journal of Medicinal Chemistry (2008), 43 (6), 1315-1320CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  
  On the basis of antibacterial anacardic acids, 6-pentadecenylsalicylic acids, isolated from the cashew apple, Anacardium occidentale L. (Anacardiaceae), a series of 6-alk(en)ylsalicylic acids were synthesized and tested for their antibacterial activity against Streptococcus mutans ATCC 25175. Among them, 6-(4',8'-dimethylnonyl)salicylic acid (I) was found to exhibit the most potent antibacterial activity against this cariogenic bacterium with the min. inhibition concn. (MIC) of 0.78 μg/mL.
  
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19. 19
  Mamidyala, S. K.; Ramu, S.; Huang, J. X.; Robertson, A. A. B.; Cooper, M. A. Efficient synthesis of anacardic acid analogues and their antibacterial activities. Bioorg. Med. Chem. Lett. 2013, 23, 1667– 1670, DOI: 10.1016/j.bmcl.2013.01.074
  
  19
  Efficient synthesis of anacardic acid analogues and their antibacterial activities
  
  Mamidyala, Sreeman K.; Ramu, Soumya; Huang, Johnny X.; Robertson, Avril A. B.; Cooper, Matthew A.
  
  Bioorganic & Medicinal Chemistry Letters (2013), 23 (6), 1667-1670CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
  
  Anacardic acid derivs. exhibit a broad range of biol. activities. In this report, an efficient method for the synthesis of anacardic acid derivs. was explored, and a small set of salicylic acid variants synthesized retaining a const. hydrophobic element (a naphthyl tail). The naphthyl side chain was introduced via Wittig reaction and the aldehyde installed using directed ortho-metalation reaction of the substituted o-anisic acids. The failure of ortho-metalation using unprotected carboxylic acid group compelled us to use directed ortho-metalation in which a tertiary amide was used as a strong ortho-directing group. In the initial route, tertiary amide cleavage during final step was challenging, but cleaving the tertiary amide before Wittig reaction was beneficial. The Wittig reaction with protected carboxylic group (Me ester) resulted in side-products whereas using sodium salt resulted in higher yields. The novel compds. were screened for antibacterial activity and cytotoxicity. Although substitution on the salicylic head group enhanced antibacterial activities they also enhanced cytotoxicity.
  
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20. 20
  Zoete, V.; Daina, A.; Bovigny, C.; Michielin, O. SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening. J. Chem. Inf. Model. 2016, 56, 1399– 1404, DOI: 10.1021/acs.jcim.6b00174
  
  20
  SwissSimilarity: A Web Tool for Low to Ultra High Throughput Ligand-Based Virtual Screening
  
  Zoete, Vincent; Daina, Antoine; Bovigny, Christophe; Michielin, Olivier
  
  Journal of Chemical Information and Modeling (2016), 56 (8), 1399-1404CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
  
  SwissSimilarity is a new web tool for rapid ligand-based virtual screening of small to unprecedented ultralarge libraries of small mols. Screenable compds. include drugs, bioactive and com. mols., as well as 205 million of virtual compds. readily synthesizable from com. available synthetic reagents. Predictions can be carried out on-the-fly using six different screening approaches, including 2D mol. fingerprints as well as superpositional and fast nonsuperpositional 3D similarity methodologies. SwissSimilarity is part of a large initiative of the SIB Swiss Institute of Bioinformatics to provide online tools for computer-aided drug design, such as SwissDock, SwissBioisostere or SwissTargetPrediction with which it can interoperate, and is linked to other well-established online tools and databases. User interface and backend have been designed for simplicity and ease of use, to provide proficient virtual screening capabilities to specialists and nonexperts in the field. SwissSimilarity is accessible free of charge or login at http://www.swisssimilarity.ch.
  
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21. 21
  Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717, DOI: 10.1038/srep42717
  
  21
  SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules
  
  Daina Antoine; Michielin Olivier; Zoete Vincent; Michielin Olivier; Michielin Olivier
  
  Scientific reports (2017), 7 (), 42717 ISSN:.
  
  To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
  
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22. 22
  Daina, A.; Zoete, V. A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem 2016, 11, 1117– 1121, DOI: 10.1002/cmdc.201600182
  
  22
  A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules
  
  Daina, Antoine; Zoete, Vincent
  
  ChemMedChem (2016), 11 (11), 1117-1121CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  
  Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to est. at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL Estd. permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small mols. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochem. descriptors and straightforwardly translated into mol. design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chem. libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.
  
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23. 23
  Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2012, 64, 4– 17, DOI: 10.1016/j.addr.2012.09.019
  
  There is no corresponding record for this reference.
24. 24
  Veber, D. F.; Johnson, S. R.; Cheng, H.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45, 2615– 2623, DOI: 10.1021/jm020017n
  
  24
  Molecular Properties That Influence the Oral Bioavailability of Drug Candidates
  
  Veber, Daniel F.; Johnson, Stephen R.; Cheng, Hung-Yuan; Smith, Brian R.; Ward, Keith W.; Kopple, Kenneth D.
  
  Journal of Medicinal Chemistry (2002), 45 (12), 2615-2623CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  
  Oral bioavailability measurements in rats for over 1100 drug candidates studied at Smith-Kline Beecham Pharmaceuticals (now Glaxo Smith-Kline) have allowed us to analyze the relative importance of mol. properties considered to influence that drug property. Reduced mol. flexibility, as measured by the no. of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of mol. wt. That on av. both the no. of rotatable bonds and polar surface area or hydrogen bond count tend to increase with mol. wt. may in part explain the success of the mol. wt. parameter in predicting oral bioavailability. The commonly applied mol. wt. cutoff at 500 does not itself significantly sep. compds. with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compds. which meet only the 2 criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area ≤140 Å2 (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examd. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a neg. effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examd. here for the in vivo clearance rate in the rat.
  
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25. 25
  Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999, 1, 55– 68, DOI: 10.1021/cc9800071
  
  25
  A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases
  
  Ghose, Arup K.; Viswanadhan, Vellarkad N.; Wendoloski, John J.
  
  Journal of Combinatorial Chemistry (1999), 1 (1), 55-68CODEN: JCCHFF; ISSN:1520-4766. (American Chemical Society)
  
  The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of org. synthesis and biochem. screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compds. in the thousands. With automated synthesis, the no. of compds. to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chem. libraries are made wisely. The objective of this work is to provide both quant. and qual. characterization of known drugs which will help to generate "drug-like" libraries. In this work the authors analyzed the Comprehensive Medicinal Chem. (CMC) database and seven different subsets belonging to different classes of drug mols. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quant. characterization based on computed physicochem. property profiles such as log P, molar refractivity, mol. wt., and no. of atoms as well as a qual. characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compds.) of the calcd. log P is between -0.4 and 5.6, with an av. value of 2.52. For mol. wt., the qualifying range is between 160 and 480, with an av. value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an av. value of 97. For the total no. of atoms, the qualifying range is between 20 and 70, with an av. value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonarom. heterocyclic rings are twice as abundant as the arom. heterocycles. Tertiary aliph. amines, alc. OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochem. properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chem. library.
  
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26. 26
  Cortes, C.; Vapnik, V. Support-Vector Networks. Mach. Learn. 1995, 20, 273– 297, DOI: 10.1023/a:1022627411411
  
  There is no corresponding record for this reference.
27. 27
  Pires, D. E. V.; Blundell, T. L.; Ascher, D. B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015, 58, 4066– 4072, DOI: 10.1021/acs.jmedchem.5b00104
  
  27
  pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures
  
  Pires, Douglas E. V.; Blundell, Tom L.; Ascher, David B.
  
  Journal of Medicinal Chemistry (2015), 58 (9), 4066-4072CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  
  Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. The authors have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. PkCSM performs as well or better than current methods. A freely accessible web server (http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties.
  
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28. 28
  Pellicciari, A. Attrition in the Pharmaceutical Industry - Reasons, Implications, and Pathways Forward. Edited by Alexander Alex, C. John Harris, Dennis A. Smith. ChemMedChem 2017, 12, 1097– 1098, DOI: 10.1002/cmdc.201600621
  
  28
  Attrition in the Pharmaceutical Industry - Reasons, Implications, and Pathways Forward. Edited by Alexander Alex, C. John Harris, Dennis A. Smith
  
  Pellicciari, Roberto
  
  ChemMedChem (2017), 12 (13), 1097-1098CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
  
  There is no expanded citation for this reference.
  
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29. 29
  van deWaterbeemd, H.; Smith, D. A.; Jones, B. C. Lipophilicity in PK design: Methyl, ethyl, futile. J. Comput.-Aided Mol. Des. 2001, 15, 273– 286, DOI: 10.1023/a:1008192010023
  
  There is no corresponding record for this reference.
30. 30
  Pliška, V.; Testa, B.; Waterbeemd, H. V. Lipophilicity in Drug Action and Toxicology; VCH Verlagsgesellschaft mbH: Weinheim (Federal Republic of Germany), 1996.
  
  There is no corresponding record for this reference.
31. 31
  Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: Misconceptions in drug discovery. Nat. Rev. Drug Discovery 2010, 9, 929– 939, DOI: 10.1038/nrd3287
  
  32
  The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery
  
  Smith, Dennis A.; Di, Li; Kerns, Edward H.
  
  Nature Reviews Drug Discovery (2010), 9 (12), 929-939CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  
  A review. Data from in vitro plasma protein binding expts. that det. the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compds. for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is detd. by the free (unbound) drug concn. surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concn. So, decisions based on free drug fraction could result in the wrong compds. being advanced through drug discovery programs. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.
  
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32. 32
  Di, L.; Kerns, E. H. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization; Elsevier publisher, 2008.
  
  There is no corresponding record for this reference.
33. 33
  Khojasteh, S. C.; Wong, H.; Hop, C. E. C. A. Pharmacokinetics. Drug Metabolism and Pharmacokinetics Quick Guide; Springer, 2011; p 1.
  
  There is no corresponding record for this reference.
34. 34
  Li, A. P.; Jurima-Romet, M. Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: Evaluation of model drugs terfenadine and rifampin. Cell Biol. Toxicol. 1997, 13, 365– 374, DOI: 10.1023/A:1007451911843
  
  35
  Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: evaluation of model drugs terfenadine and rifampin
  
  Li, A. P.; Jurima-Romet, M.
  
  Cell Biology and Toxicology (1997), 13 (4/5), 365-374CODEN: CBTOE2; ISSN:0742-2091. (Kluwer)
  
  The utility of primary human hepatocytes in the evaluation of drug-drug interactions is being investigated in our labs. Our initial approach was to investigate whether drug-drug interactions obsd. in humans in vivo could be reproduced in vitro using human hepatocytes. Two model drugs were studied: terfenadine and rifampin, representing compds. subjected to drug-drug interactions via inhibitory and induction mechanisms, resp. Terfenadine was found to be metabolized by human hepatocytes to C-oxidn. and N-dealkylation products as obsd. in humans in vivo. Metab. by human hepatocytes was found to be inhibited by drugs which are known to be inhibitory in vivo. Ki values for the various inhibitors were derived from the in vitro metab. data, resulting in the following ranking of inhibitory potency: For the inhibition of C-oxidn., ketoconazole > itraconazole > cyclosporin ∼ troleandomycin > erythromycin > naringenin. For the inhibition of N-dealkylation, itraconazole ≥ ketoconazole > cyclosporin ≥ naringenin ≥ erythromycin ≥ troleandomycin. Rifampin induction of CYP3A, a known effect of rifampin in vivo, was also reproduced in primary human hepatocytes. Induction of CYP3A4, measured as testosterone 6β-hydroxylation, was found to be dose-dependent, treatment duration-dependent, and reversible. The induction effect of rifampin was obsd. in hepatocytes isolated from all 7 human donors studied, with ages ranging from 1.7 to 78 yr. To demonstrate that the rifampin-induction of testosterone 6β-hydroxylation could be generalized to other CYP3A4 substrates, we evaluated the metab. of another known substrate of CYP3A4, lidocaine. Dose-dependent induction of lidocaine metab. by rifampin is obsd. Our results suggest that primary human hepatocytes may be a useful exptl. system for preclin. evaluation of drug-drug interaction potential during drug development, and as a tool to evaluate the mechanism of clin. obsd. drug-drug interactions.
  
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35. 35
  Danielsson, B. R.; Lansdell, K.; Patmore, L.; Tomson, T. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res. 2003, 55, 147– 157, DOI: 10.1016/s0920-1211(03)00119-0
  
  36
  Phenytoin and phenobarbital inhibit human HERG potassium channels
  
  Danielsson, Bengt R.; Lansdell, Kate; Patmore, Leslie; Tomson, Torbjorn
  
  Epilepsy Research (2003), 55 (1-2), 147-157CODEN: EPIRE8; ISSN:0920-1211. (Elsevier Science B.V.)
  
  Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (IKr) channel can be proarrhythmic and their clin. use has been assocd. with sudden unexpected death (SUD). Since SUD is about 20 times more common among people with epilepsy than in the general population, and some data indicate that drug treatment may contribute, we tested the hypothesis that the classic antiepileptic drugs phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) have a potential to block IKr. The whole cell patch-clamp recording technique was used to study the effects on IKr channels expressed by the human ether-a-go-go related gene (HERG) stably expressed in Human Embryo Kidney (HEK) 293 cells. Tail currents, which are purely related to HERG, were blocked with an IC50 (the concn. when 50% inhibition was obtained compared to control values) of 240 μM for PHT and 3 mM for PB. A 20% inhibition of tail currents was obtained at CBZ concns. of 250 and 500 μM. Collective data show that drugs with the same margins (ratio HERG IC50/unbound therapeutic concn.), as PHT and PB, may have arrhythmogenic potential, esp. when used in predisposed patients and in the case of drug-drug interactions. SUD in epilepsy is generally a seizure-related phenomenon. However, our data suggest that PHT and PB may play a contributing role, perhaps by making some patients more vulnerable to the cardiovascular depression induced by seizures.
  
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36. 36
  Hosey, C. M.; Benet, L. Z. Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions. Mol. Pharm. 2015, 12, 1456– 1466, DOI: 10.1021/mp500783g
  
  37
  Predicting the Extent of Metabolism Using in Vitro Permeability Rate Measurements and in Silico Permeability Rate Predictions
  
  Hosey, Chelsea M.; Benet, Leslie Z.
  
  Molecular Pharmaceutics (2015), 12 (5), 1456-1466CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  
  The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metab. and soly. of a drug. However, defining the extent of metab. relies upon clin. data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, the authors aimed to det. if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metab., to det. a ref. compd. representing the permeability rate above which compds. would be expected to be extensively metabolized, and to predict the major route of elimination of compds. in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calcd. using ADMET Predictor or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compds. was analyzed with receiver operating characteristic curves. Compds. that yielded the highest sensitivity-specificity av. were selected as permeability rate ref. stds. The major route of elimination of poorly permeable drugs was predicted by the authors' previously published model, and the accuracies and predictive values were calcd. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metab. of compds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco-2 and MDCK, resp., while theophylline predicted greater than 80% of extensively and poorly metabolized drugs correctly in PAMPA. A two-tier approach predicting elimination route predicts 72±9%, 49±10%, and 66±7% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is predicted in silico and 74±7%, 85±2%, and 73±8% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is detd. in vitro.
  
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37. 37
  Czechtizky, C.; Hamley, P. Small Molecule Medicinal Chemistry: Strategies and Technologies; John Wiley & Sons, 2015.
  
  There is no corresponding record for this reference.
38. 38
  Singh, U.; Gangwal, R. P.; Dhoke, G. V.; Prajapati, R.; Damre, M.; Sangamwar, A. T. 3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors. Arabian J. Chem. 2017, 10, S617– S626, DOI: 10.1016/j.arabjc.2012.10.023
  
  39
  3D-QSAR and molecular docking analysis of (4-piperidinyl)-piperazines as acetyl-CoA carboxylases inhibitors
  
  Singh, Udghosh; Gangwal, Rahul Prakashchand; Dhoke, Gaurao V.; Prajapati, Rameshwar; Damre, Mangesh; Sangamwar, Abhay T.
  
  Arabian Journal of Chemistry (2017), 10 (Suppl._1), S617-S626CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)
  
  Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme, which plays a vital role in fatty acid metab. and obesity induced type 2 diabetes. Herein, we have performed 3D-QSAR and mol. docking anal. on a novel series of (4-piperidinyl)-piperazines to design potent ACC inhibitors. This study correlates the ACC inhibitory activities of 68 (4-piperidinyl)-piperazine derivs. with several stereo-chem. parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The CoMFA and CoMSIA models exhibited excellent r2ncv values of 0.974 and 0.985, and r2cv values of 0.671 and 0.693, resp. CoMFA predicted r2pred of 0.910 and CoMSIA predicted r2pred of 0.963 showed that the predicted values were in good agreement with exptl. values. Glide5.5 program was used to explore the binding mode of inhibitors inside the active site of ACC. We have accordingly designed novel ACC inhibitors by utilizing the LeapFrog and predicted with excellent inhibitory activity in the developed models.
  
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39. 39
  Bendaif, H.; Melhaoui, A.; Ramdani, M.; Elmsellem, H.; Douez, C.; El Ouadi, Y. Antibacterial activity and virtual screening by molecular docking of lycorine from Pancratium foetidum Pom (Moroccan endemic Amaryllidaceae). Microb. Pathog. 2018, 115, 138– 145, DOI: 10.1016/j.micpath.2017.12.037
  
  40
  Antibacterial activity and virtual screening by molecular docking of lycorine from Pancratium foetidum Pom (Moroccan endemic Amaryllidaceae)
  
  Bendaif, H.; Melhaoui, A.; Ramdani, M.; Elmsellem, H.; Douez, C.; El Ouadi, Y.
  
  Microbial Pathogenesis (2018), 115 (), 138-145CODEN: MIPAEV; ISSN:0882-4010. (Elsevier Ltd.)
  
  Lycorine is an alkaloid isolated from bulbs of Pancratium foetidum Pom Amaryllidaceae of the genus Lycoris. It has very strong pharmacodynamics properties and biol. effects, among others, antimalarial, antiviral, antitumor, and anti-inflammatory. Lycorine has been identified and characterized by thin layer chromatog., IR and NMR (1H and 13C NMR, COZY, HMBC, HSQC and NOESY). The antibacterial activity of lycorine has been evaluated. Lycorine has a moderate antibacterial activity on the majority of strains studied, nevertheless it is more effective than Streptomycin and Ampicillin against bacteria: P. aeruginosa, En. cloacae. To confirm these results, it is necessary to use qual. techniques and methods, etc... We performed a virtual docking ligand-lycorine protein screening study to predict and characterize their mode of interaction with the LpxC receptor. Docking results have shown that lycorine can interact with target amino residues studied by hydrogen and metal-ion bonds. In addn., the ADME-Tox profile study has shown that lycorine is all in agreement, either with Lipinski's critics or with the toxicity stds.
  
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40. 40
  Karthick, T.; Tandon, P. Computational approaches to find the active binding sites of biological targets against busulfan. J. Mol. Model. 2016, 22, 142, DOI: 10.1007/s00894-016-3015-z
  
  41
  Computational approaches to find the active binding sites of biological targets against busulfan
  
  Karthick T; Tandon Poonam
  
  Journal of molecular modeling (2016), 22 (6), 142 ISSN:.
  
  Determination of electrophilic and nucleophilic sites of a molecule is the primary task to find the active sites of the lead molecule. In the present study, the active sites of busulfan have been predicted by molecular electrostatic potential surface and Fukui function analysis with the help of dispersion corrected density functional theory. Similarly, the identification of active binding sites of the proteins against lead compound plays a vital role in the field of drug discovery. Rigid and flexible molecular docking approaches are used for this purpose. For rigid docking, Hex 8.0.0 software employing fast Fourier transform (FFT) algorithm has been used. The partial flexible blind docking simulations have been performed with AutoDock 4.2 software; where a Lamarckian genetic algorithm is employed. The results showed that the most electrophilic atoms of busulfan bind with the targets. It is clear from the docking studies that busulfan has inhibition capability toward the targets 12CA and 1BZM. Graphical Abstract Docking of ligand and protein.
  
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41. 41
  Shaikh, S.; Shastri, S. L.; Naik, N. S.; Kulkarni, R.; Madar, J. M.; Shastri, L. A.; Joshi, S. D.; Sunagar, V. Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies. ChemistrySelect 2019, 4, 105– 115, DOI: 10.1002/slct.201802395
  
  42
  Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies
  
  Shaikh, Farzanabi; Shastri, Samundeeswari L.; Naik, Nirmala S.; Kulkarni, Rashmi; Madar, Jyoti M.; Shastri, Lokesh A.; Joshi, Shrinivas D.; Sunagar, Vinay
  
  ChemistrySelect (2019), 4 (1), 105-115CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)
  
  A series of substituted coumarin-1,2,4-triazolidine-3-thiones such as I [R = 7-Me, 6-Cl, 7,8-di-Me, etc.] and phenyl-1,2,4-triazolidine-3-thiones such as II [R = 4-Me2N, 3-HO-4-MeO, 4-Br-2-HO, etc.] was synthesized and evaluated for their antitubercular and antimicrobial activities. Most of the compds. I and II showed promising antitubercular activity against Mycobacterium tuberculosis. The title compds. I and II exhibited excellent in vitro antibacterial and antifungal activities. Mol. docking study was performed for all the synthesized compds. I and II with E.coli as antibacterial and Mycobacterium tuberculosis DprE1 as antituberculosis.
  
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42. 42
  Sidhu, A.; Kukreja, S. Synthesis of novel fluorinated benzothiazol-2-yl-1,2,4-triazoles: Molecular docking, antifungal evaluation and in silico evaluation for SAR. Arabian J. Chem. 2019, 12, 2118, DOI: 10.1016/j.arabjc.2015.01.009
  
  There is no corresponding record for this reference.
43. 43
  Kareem, A.; Nami, S. A. A.; Khan, M. S.; Bhat, S. A.; Mirza, A. U.; Nishat, N. Self-assembled transition metal dithiocarbamates of pyridine-3-carboxamide: synthesis, spectral characterization, thermal and biological studies. New J. Chem. 2019, 43, 4413, DOI: 10.1039/c8nj03660h
  
  44
  Self-assembled transition metal dithiocarbamates of pyridine-3-carboxamide: synthesis, spectral characterization, thermal and biological studies
  
  Kareem, Abdul; Nami, Shahab A. A.; Khan, Mohd Shoeb; Bhat, Shahnawaz Ahmad; Mirza, Azar Ullah; Laxmi; Nishat, Nahid
  
  New Journal of Chemistry (2019), 43 (11), 4413-4424CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  
  A novel bidentate dithiocarbamate ligand (ndtc) derived from pyridine-3-carboxamide, (nicotinamide) by the insertion reaction of CS2 and its subsequent self-assembled 1st row transition metal complexes M(ndtc)2 [where M = Co(II), Ni(II), Cu(II), and Zn(II) ions] was synthesized and characterized using various spectral techniques. The facile reaction between the transition metal halide and ndtc in a 1 : 2 molar ratio yielded the aforesaid complexes in high yields. The formation of a single product was confirmed by thin layer chromatog. CHNS, IR, NMR spectra (1H and 13C), TGA/DTA, XRD, UV-visible spectra, magnetic moment, and cond. measurements were performed to ascertain the proposed structure of the synthesized complexes. From the abovementioned studies, the complexes possess an octahedral arrangement, except for the Cu(II) ion, which has a square-planar structure. The dithiocarbamate moiety was found to coordinate in a bidentate sym. fashion with the metal ions in all the complexes. The complexes were screened against a variety of human cancer cell lines such as human hepatocellular carcinoma (Hep3B), human breast adenocarcinoma (MCF7), and normal cells (PBMC). The complexes displayed moderate to good cytotoxicity on these cancer cell lines. However, Cu(ndtc)2 is most potent on MCF7, with an IC50 value, 3.56 ± 1.1500, while Zn(ndtc)2 was the most potent against liver and cervical cancer cell lines, with IC50 values, 2.32 ± 1.5000 and 3.58 ± 1.6100 in micro-molar concns., resp. The antioxidant potential of the ndtc and its metal complexes was detd. using DPPH, and Cu(ndtc)2 is most efficient. Also, mol. docking simulations were also performed for the ndtc and its complexes, which confirmed the findings of the cytotoxicity.
  
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44. 44
  Kaviyarasi, N. S.; Prashantha, C. N.; Suryanarayana, V. V. S. In Silico Analysis of Inhibitor and Substrate Binding Site of Serrapeptidase from Serratia Marcescens MTCC 8708. Int. J. Pharmacol. Pharm. Sci. 2016, 8, 123– 128
  
  45
  In silico analysis of inhibitor and substrate binding site of serrapeptidase from Serratia marcescens MTCC 8708
  
  Kaviyarasi, N. S.; Prashantha, C. N.; Suryanarayana, V. V. S.
  
  International Journal of Pharmacy and Pharmaceutical Sciences (2016), 8 (4), 123-128CODEN: IJPPKB; ISSN:0975-1491. (Innovare Academic Sciences Pvt. Ltd.)
  
  Objective: Serrapeptidase is a therapeutic enzyme broadly used as an anti-inflammatory drug to treat inflammatory diseases like arthritis, bronchitis, fibrocystic breast disease and sinusitis. The objective of present study is in silco analyzes of the substrate and inhibitor binding sites of serratiopeptidase, expressed from a cloned gene. Methods: The gene encoding Serrapeptidase was amplified from genomic DNA of Serratia marcescens MTCC 8707, an isolated from the flowers of summer squash plants. The gene was sequenced, the nucleotide sequence of 1464 nucleotides was submitted to Gen Bank nucleotide database and accession no. GI: KP869847 obtained. The develop amino acid sequence was used to predict 3D structure using different bioinformatics tools and software's Further, CABS-dock and Swiss Dock, the docking servers were used for enzyme-substrate/inhibitor binding site anal. The inflammatory mediators, bradykinin, and substance-P were used as substrates, whereas, EDTA and Lisinopril were used as an inhibitor for serrapeptidase. UCSF Chimera program was used for interactive visualization and anal. of docked results. Results: The docking studies show substrates bradykinin and substance-P bind near zinc binding site with min. RMSD value and the inhibitors EDTA and lisinopril showed favorable interaction at zinc binding site of serrapeptidase with min. free energy. Conclusion: The result of docking studies confirm that the substrate or inhibitor binds near zinc binding domain (HEXXH.) and the peptide bond of the substrate can be effectively cleaved by serrapeptidase.
  
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45. 45
  De Vita, D.; Pandolfi, F.; Ornano, L.; Feroci, M.; Chiarotto, I.; Sileno, I.; Pepi, F.; Costi, R.; Di Santo, R.; Scipione, L. New N,N-Dimethylcarbamate Inhibitors of Acetylcholinesterase: Design Synthesis and Biological Evaluation. J. Enzyme Inhib. Med. Chem. 2016, 31, 106– 113, DOI: 10.1080/14756366.2016.1220377
  
  46
  New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation
  
  De Vita, Daniela; Pandolfi, Fabiana; Ornano, Luigi; Feroci, Marta; Chiarotto, Isabella; Sileno, Ilaria; Pepi, Federico; Costi, Roberta; Di Santo, Roberto; Scipione, Luigi
  
  Journal of Enzyme Inhibition and Medicinal Chemistry (2016), 31 (sup4), 106-113CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
  
  A series of N,N-dimethylcarbamates contg. a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compds. 4 and 8, showed 85 and 69% of inhibition at 50 μM, resp. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aroms. rings of the dibenzylamino group reduce the inhibitory power. Compd. 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compd. 4 and by MALDI-TOF MS anal. of trypsinized AChE inhibited by compd. 4. Instead, compd. 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.
  
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46. 46
  Iftikhar, H.; Batool, S.; Deep, A.; Narasimhan, B.; Sharma, P. C.; Malhotra, M. In Silico Analysis of the Inhibitory Activities of GABA Derivatives on 4-Aminobutyrate Transaminase. Arabian J. Chem. 2017, 10, S1267– S1275, DOI: 10.1016/j.arabjc.2013.03.007
  
  47
  In silico analysis of the inhibitory activities of GABA derivatives on 4-aminobutyrate transaminase
  
  Iftikhar, Hira; Batool, Sidra; Deep, Aakash; Narasimhan, Balasubramanian; Sharma, Prabodh Chander; Malhotra, Manav
  
  Arabian Journal of Chemistry (2017), 10 (Suppl._1), S1267-S1275CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)
  
  Reduced levels of γ-aminobutyric acid (GABA) are cause of quite a many diseases, and it cannot be directly introduced into the body to enhance its level because of the blood-brain barrier. Thus the technique used for the purpose involves the inhibition of aminobutyrate transaminase (ABAT), the enzyme catalyzing its degrdn. The structure of human ABAT is not currently known exptl., thus, it was predicted by homol. modeling using pig ABAT as template due to high level of sequence similarity and conservation. A series of new γ-aminobutyric acid (GABA) derivs. obtained from 4-(1,3-dioxoisoindolin-2-yl)butanoic acid are used in this study. These γ -aminobutyric acid (GABA) derivs. were used as ligand dockings against human ABAT as well as pig ABAT receptors.
  
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47. 47
  Chhajed, S. S.; Upasani, C. D. Synthesis, Biological Screening and Molecular Modeling Studies of Novel 3-Chloro-4-Substituted-1-(2-(1H-Benzimidazol-2-Yl)Phenyl))-Azetidin-2-Ones. J. Enzyme Inhib. Med. Chem. 2012, 27, 504, DOI: 10.3109/14756366.2011.598867
  
  48
  Synthesis, biological screening and molecular modeling studies of novel 3-chloro-4-substituted-1-(2-(1H-benzimidazol-2-yl)phenyl)-azetidin-2-ones
  
  Chhajed, Santosh S.; Upasani, Chandrashekhar D.
  
  Journal of Enzyme Inhibition and Medicinal Chemistry (2012), 27 (4), 504-508CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)
  
  In the present investigation synthesis of some novel 1-(2-(1H-benzimidazol-2-yl)phenyl)-3-chloro-4-(Un/substituted phenyl)azetidin-2-one antibacterial are reported. Structures of synthesized compds. were confirmed by spectral techniques (IR, Mass, 1H-NMR) All reactions were monitored with anal. thin layer chromatog. Synthesized compds. were docked in to the active site of enzyme transpeptidase. Four compds. were found to have good affinity for transpeptidase with potent antibacterial activity. A good correlation is found between in silico docking anal. and in vitro antibacterial activity.
  
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  Rege, M. D.; Ghadi, R.; Katiyar, S. S.; Kushwah, V.; Jain, S. Exploring an interesting dual functionality of anacardic acid for efficient paclitaxel delivery in breast cancer therapy. Nanomedicine 2019, 14, 57, DOI: 10.2217/nnm-2018-0138
  
  49
  Exploring an interesting dual functionality of anacardic acid for efficient paclitaxel delivery in breast cancer therapy
  
  Rege, Madhura D.; Ghadi, Rohan; Katiyar, Sameer S.; Kushwah, Varun; Jain, Sanyog
  
  Nanomedicine (London, United Kingdom) (2019), 14 (1), 57-75CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)
  
  To explore the potential of paclitaxel (PTX)-loaded anacardic acid conjugated hydrophobized gelatin nanoparticles. Nanoparticles prepd. by nanopptn. technique were evaluated for various quality attributes (particle size, % entrapment efficiency) in vitro drug release, MCF-7 cell uptake, cell cytotoxicity, in vivo pharmacokinetics, antitumor efficacy and toxicity. The nanoparticles (250-300 nm, 74% entrapment efficiency) showed approx. 2.26-fold higher apoptosis index and approx. 5.86-fold redn. in IC50 value compared with PTX in MCF-7 cells. Also, approx. 3.51- and 1.36-fold increase in area under the curve compared with Intaxel and Nanoxel (both from Fresenius Kabi, Gurugram, India) was achieved. Significant tumor burden redn. (∼60%) and reduced toxicity was obsd. compared with marketed formulations. The hydrophobized gelatin nanoparticles displayed promising therapeutic potential, paving a new path for efficient PTX delivery.
  
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- PDB: 1W98
- PDB: 1w98
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b04398.
- Chemical structures of alkyl chain-modified AA derivatives (labeled from 1 to 29); chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 30 to 49; chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 50 to 76; chemical structures of alkyl chain- and functional group-modified AA derivatives labeled from 77 to 100; BOILED-Egg model of AA1–AA100 derivatives; important computed physicochemical properties for AA1–AA100; important computed ADMET properties for AA1–AA100 derivatives; and computed safety end points for AA1–AA100 derivatives (PDF)
- ao9b04398_si_001.pdf (933.12 kb)
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Physicochemical and Pharmacokinetic Analysis of Anacardic Acid Derivatives

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Abstract

1. Introduction

Figure 1

2. Materials and Methods

3. Results and Discussion

3.1. Structural and Physicochemical Properties

Figure 2

3.2. Comparison of Physicochemical Properties of AA Derivatives with Marketed Anticancer Drugs

3.3. BOILED-Egg for Prediction of GI Absorption and Brain Penetration

Figure 3

3.4. Prediction of ADMET and Related Properties

3.5. Molecular Docking Studies

Figure 4

4. Conclusions

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Abstract

Figure 1

Figure 2

Figure 3

Figure 4

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STEP 1:

STEP 2: