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The reaction coordinate of the fragmentation of aromatic radical anions with nucleofugal groups was studied by the INDO and MNDO techniques. The reaction coordinate turned out as the stretching between the nucleofugal group bonded to the... more
The reaction coordinate of the fragmentation of aromatic radical anions with nucleofugal groups was studied by the INDO and MNDO techniques. The reaction coordinate turned out as the stretching between the nucleofugal group bonded to the carbon atom of the aryl moiety. It was found that to fragment a π* radical anion, the odd electron has to be transferred to the σ* molecular orbital of the aryl-nucleofugal bond by an orbital crossing, which is reached by the lengthening of this bond. There is a qualitative agreement between the length of the bond to reach the orbital crossing point and the experimental fragmentation rates of the aromatic radical anions. Finally, some considerations about the σ-π coupling are made, since it is defining the possibility of a transfer from the π* to the σ* molecular orbital.
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ABSTRACT
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Abstract This article addresses the systematic and complete enumeration of all the substructures of any size present in a given molecule. The study is not restricted to features which could be defined a priori such as rings or chains.... more
Abstract This article addresses the systematic and complete enumeration of all the substructures of any size present in a given molecule. The study is not restricted to features which could be defined a priori such as rings or chains. Contrary to prior expectation the ...
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Abstract An extension of our previous work on the development of a conformationally dependent hydrophobic index is presented. The parameter was computed in four alternative ways based on steric parameters, such as the total molecular... more
Abstract An extension of our previous work on the development of a conformationally dependent hydrophobic index is presented. The parameter was computed in four alternative ways based on steric parameters, such as the total molecular surface area or the solvent ...
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Rapid expansion in the number of plausible drug targets arising from genomics research has created new pressures for increased efficiency in discovery of high specificity candidate drug compounds. Improved understanding of conserved... more
Rapid expansion in the number of plausible drug targets arising from genomics research has created new pressures for increased efficiency in discovery of high specificity candidate drug compounds. Improved understanding of conserved features among protein structures provides a promising route to achieving this goal. Indirect evidence implies that important similarities are now ripe for elucidation by emerging experimental approaches.
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A theoretical study of the reaction coordinate for the coupling of phenyl radical with methyl anion, chloride and fluoride ions to yield the corresponding radical anion is carried out. In this process, σ and σ* MO's associated to the... more
A theoretical study of the reaction coordinate for the coupling of phenyl radical with methyl anion, chloride and fluoride ions to yield the corresponding radical anion is carried out. In this process, σ and σ* MO's associated to the new bond are formed. The σ* MO is the lowest lying of the system for the radical anion formed in the coupling with chloride ion. With methyl anion and fluoride ion, σ and σ* MO's are also formed, but before they reach the equilibrium distance of the radical anion intermediate, the π* MO equals its energy with the incipient σ*, and from there on to the equilibrium distance, the odd electron stays in the π* MO.
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Chemistry, Photochemistry, Fluoride, Decomposition, Canadian, and 3 moreChloride, CHEMICAL SCIENCES, and Ion
An analysis of amino acid composition of small, naturally occurring peptides ranging in size from 3 to 50 residues has been carried out. The purpose of the study is to determine whether differential trends in amino acid usage exist for... more
An analysis of amino acid composition of small, naturally occurring peptides ranging in size from 3 to 50 residues has been carried out. The purpose of the study is to determine whether differential trends in amino acid usage exist for small peptides compared to larger polypeptides and proteins. Results indicate that Cys, Trp, and Phe are substantially more frequent in peptides compared to their abundance in proteins at large. Aliphatic hydrophobic residues, particularly Leu and Ile, are somewhat underrepresented, while the frequency of Glu is significantly reduced. The shorter peptides are also more frequently neutral and become increasingly charged as their size increases.
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A self consistent reaction field study has been carried out at the MINDO/3 level, in order to explain the decomposition of the species in solution.
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Compounds that bind with significant affinity to the opioid receptor types, delta, mu, and kappa, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working... more
Compounds that bind with significant affinity to the opioid receptor types, delta, mu, and kappa, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types delta, mu, or kappa were identified. Using a distance analysis approach, common geometric arrangements of these chemical moieties were found for selected delta, mu, or kappa opioid agonists. The chemical and geometric commonalities among agonists at each opioid receptor type were then compared with a non-specific opioid recognition pharmacophore recently developed. The comparison provided identification of the additional requirements for activation of delta, mu, and kappa opioid receptors. The distance analysis approach was able to clearly discriminate kappa-agonists, while global molecular properties for all compounds were calculated to identify additional requirements for activation of delta and mu receptors. Comparisons of the combined geometric and physicochemical properties calculated for each of the three sets of agonists allowed the determination of unique requirements for activation of each of the three opioid receptors. These results can be used to improve the activation selectivity of known opioid agonists and as a guide for the identification of novel selective opioid ligands with potential therapeutic usefulness.
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ABSTRACT This report describes the existence of statistical relationships among scores computed with the DOCK program for a library of small molecules and a panel of protein binding sites. Multivariate relationships are observed in... more
ABSTRACT This report describes the existence of statistical relationships among scores computed with the DOCK program for a library of small molecules and a panel of protein binding sites. Multivariate relationships are observed in docking scores computed for a constant set of ligands in different binding sites of proteins that are dissimilar in structure and function. The structural basis for the correlations found among scores is analyzed in terms of size, shape and charge characteristics of the binding sites considered. Interestingly, these results parallel a growing body of evidence demonstrating the promiscuous behavior of small molecules in their interactions with macromolecules that could have an impact in future efforts in drug design.
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Classification methods based on linear discriminant analysis, recursive partitioning, and hierarchical agglomerative clustering are examined for their ability to separate active and inactive compounds in a diverse chemical database.... more
Classification methods based on linear discriminant analysis, recursive partitioning, and hierarchical agglomerative clustering are examined for their ability to separate active and inactive compounds in a diverse chemical database. Topology-based descriptions of chemical structure from the Molconn-X and ISIS programs are used in conjunction with these classification techniques to identify ACE inhibitors, beta-adrenergic antagonists, and H2 receptor antagonists. Overall, discriminant analysis misclassifies the smallest number of active compounds, while recursive partitioning yields the lowest rate of misclassification among inactives. Binary structural keys from the ISIS package are found to generally outperform the whole-molecule Molconn-X descriptors, especially for identification of inactive compounds. For all targets and classification methods, sensitivity toward active compounds is increased by making repetitive classification using training sets that contain equal numbers of a...
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This review is intended to describe some of the methods and procedures used for computer-aided drug design when the structure of the macromolecular target is unknown, as is the case for CNS active drugs. Strategies and methods used in... more
This review is intended to describe some of the methods and procedures used for computer-aided drug design when the structure of the macromolecular target is unknown, as is the case for CNS active drugs. Strategies and methods used in computer-aided design of drugs in such instances must be "indirect," i.e., focusing on the characterization of the ligands themselves. This situation is different from one in which the three-dimensional structure of the macromolecular target for a drug is known, for example, for drugs that are enzyme inhibitors, allowing "direct" characterization of ligand-receptor interactions. Two qualitatively different "indirect" approaches are described here. One, called 2D-QSAR, is briefly reviewed. It is based on delineating regression relationships between a specified biological end point and properties of the compounds eliciting it. The other, based on pharmacophore development, constitutes the main part of this review. Several le...
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Molecular Biology, Catalysis, Macromolecular X-Ray Crystallography, Molecular, Crystal structure, and 20 moreHumans, Mice, Animals, Glutathione, Root-Mean Square Error, Enzyme, Hydrogen Bond, High Resolution, PEG, Active site, Swine, Isoenzymes, Mes, Glutathione Transferase, Protein Binding, X Ray Crystallography, Binding Site, Conformational Change, Biochemistry and cell biology, and Dimerization
The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its evaluation as a candidate for development.... more
The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its evaluation as a candidate for development. Those factors are being brought into bear earlier in the discovery process and even into the design of libraries for screening. The purpose of our study is the comparative analysis of simple physical characteristics of compounds that have been reported to be mutagens and nonmutagenic ones. The analysis of differences can lead to the development of knowledge-based biases in the libraries designed for massive screening. For each of four Salmonella strains, TA-98, TA-100, TA-1535, and TA-1537, an analysis of the statistical significance of the deviance of the averages for a number of global properties was carried out. The properties studied included parameters, such as topological indices, and bit strings representing the presence or absence of certain chemical moieties. The results suggest that mutagens display a larger number of hydrogen bond acceptor centers for most strains. Moreover, the use of bit strings points to the importance of certain molecular fragments, such a nitro groups, for the outcome of a mutagenicity study. Development of multivariate models based on global molecular properties or bit strings point to a small advantage of the latter for the prediction of mutagenicity. The benefits of the bit strings are in accord with the use of fragment-based approaches for the prediction of carcinogenicity and mutagenicity in methods described in the literature.
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The Similarity Principle provides the conceptual framework behind most modern approaches to library sampling and design. However, it is often the case that compounds which appear to be very similar structurally may in fact exhibit quite... more
The Similarity Principle provides the conceptual framework behind most modern approaches to library sampling and design. However, it is often the case that compounds which appear to be very similar structurally may in fact exhibit quite different activities ...
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... JUAN J. PEREZ: GILDA H. LOEW, AND HUGO 0. VILLAR Molecular Research Institute, 845 Page Mill Road, Palo Alto, California 94304 ... structures, 21 per initial structure, constituted the first working set of conformations, from which... more
... JUAN J. PEREZ: GILDA H. LOEW, AND HUGO 0. VILLAR Molecular Research Institute, 845 Page Mill Road, Palo Alto, California 94304 ... structures, 21 per initial structure, constituted the first working set of conformations, from which 10-15 conformations within 3-5 kcal/mol of the ...
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Abstract In this study, the techniques of computational chemistry were used to probe the origin of the differing pharmacological profiles found as a result of two simple modifications of the enkephalin analog TyrDAlaGlyPheMetNH 2: the... more
Abstract In this study, the techniques of computational chemistry were used to probe the origin of the differing pharmacological profiles found as a result of two simple modifications of the enkephalin analog TyrDAlaGlyPheMetNH 2: the presence or absence of N-...
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... Marta Filizola ∗ , Hugo O. Villar & Gilda H. Loew Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, CA 94043, USA ... Com-pounds were classified as agonists if they displayed an IC50 of 110 nM... more
... Marta Filizola ∗ , Hugo O. Villar & Gilda H. Loew Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, CA 94043, USA ... Com-pounds were classified as agonists if they displayed an IC50 of 110 nM or better at any opioid recep-tor type from the set of previous ...
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Triad Therapeutics’ proprietary technologies enable dramatic increases in both the speed of lead compound generation and the quality (binding affinity and specificity) of the compounds produced. Triad's approach, called Integrated... more
Triad Therapeutics’ proprietary technologies enable dramatic increases in both the speed of lead compound generation and the quality (binding affinity and specificity) of the compounds produced. Triad's approach, called Integrated Object-oriented PharmacoEngineering (IOPE™), focuses on designing inhibitors for entire protein families, such as oxidoreductases and kinases, thereby enabling parallel discovery of inhibitors for multiple targets within a protein family. The
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Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR... more
Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR autophosphorylation should, therefore, be useful for treating type 2 diabetes. This report describes the effect of a small molecule IR sensitizer, TLK16998, on IR signaling. This compound activated the tyrosine kinase domain of the IR beta-subunit at concentrations of 1 micromol/l or less but had no effect on insulin binding to the IR alpha-subunit even at much higher concentrations. TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. Phosphopeptide mapping revealed that the effect of TLK16998 on the IR was associated with increased tyrosine phosphorylation of the activation loop of the beta-subunit tyrosine kinase domain. TLK16998 also increased the potency of insulin in stimulating 2-deoxy-D-glucose uptake in 3T3-L1 adipocytes, with a detectable effect at 8 micromol/l and a 10-fold increase at 40 micromol/l. In contrast, only small effects were observed on IGF-1-stimulated 2-deoxy-D-glucose uptake. In diabetic mice, TLK16998, at a dose of 10 mg/kg, lowered blood glucose levels for up to 6 h. These results suggest, therefore, that small nonpeptide molecules that directly sensitize the IR may be useful for treating type 2 diabetes.
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Organic Chemistry, Statistical Analysis, Drug Discovery, Ligand Binding, Drug Design, and 16 moreRegression Analysis, Protein structure, Proteins, Affinity chromatography, Enzyme, Multivariate Regression, Protein Conformation, Analog Computation, Biological activity, Linear Regression, Chemistry Biology, Protein Binding, Ligands, Organic Compound, Protein Biosynthesis, and Biochemistry and cell biology
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In this work, the results of a simple model aimed at explaining the overall distribution of conformational minima for a chain molecule are presented. The model assumes that the conformations can be described in terms of rotational isomers... more
In this work, the results of a simple model aimed at explaining the overall distribution of conformational minima for a chain molecule are presented. The model assumes that the conformations can be described in terms of rotational isomers associated with each ...
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The ultimate goal of discovery screening is to have a fast and cost-effective strategy to meet the demands of producing high-content lead series with improved prospects for clinical success. While high-throughput screening (HTS) dominates... more
The ultimate goal of discovery screening is to have a fast and cost-effective strategy to meet the demands of producing high-content lead series with improved prospects for clinical success. While high-throughput screening (HTS) dominates the drug discovery landscape, other processes and technologies have emerged, including high-content screening and fragment-based design to provide alternatives that may be more suitable for certain targets. There has been a growing interest in reducing the number of compounds to be screened to prevent the escalation in the costs, time and resources associated with HTS campaigns. Library design plays a central role in these efforts. This opinion provides a survey of some recent developments in the diversity based library design process, but within a historical context. In particular, the importance of chemotyping and substructure analysis and the challenges presented by novel lead discovery technologies that require the design of libraries for screening are discussed. Readers will gain an appreciation of some developments in the field of library design and the factors that are driving the development of new library design technologies; specifically, challenges presented for chemoinformatics with the novel screening technologies in diversity based screening and compound filtering. Chemotyping and substrutural analysis are techniques that have been underutilized in the process of library design. However, they offer a direct way to evaluate libraries and have been successfully used to develop predictive methodologies. Tools are available to this end, but the full power of the approach has not been realized yet.
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Protein Folding, Protein Science, Biological Sciences, Molecular Recognition, Enzymes, and 13 moreMycobacterium tuberculosis, Mathematical Sciences, Oxidoreductases, Cluster Analysis, Nitrate Reductase, Proteins, Protein Sequence Analysis, Protein Conformation, Amino Acid Sequence, NAD, Proteome, Ligands, and Flavins
... Substructural Analysis in Drug Discovery Hugo O. Villar*, Mark R. Hansen and Richard Kho Altoris, Inc., 11575 Sorrento Valley Rd., San Diego, CA 92121, USA Abstract: The dominant paradigm in drug discovery emphasizes techniques that... more
... Substructural Analysis in Drug Discovery Hugo O. Villar*, Mark R. Hansen and Richard Kho Altoris, Inc., 11575 Sorrento Valley Rd., San Diego, CA 92121, USA Abstract: The dominant paradigm in drug discovery emphasizes techniques that generate large amounts of data. ...
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Page 1. Theoret. Chim. Acta (Berl.) 64, 313-316 (1984) THEORETICA CHIMICA ACTA 9 Springer-Verlag 1984 A theoretical study of the relative stability of the isomeric forms of NzO3 Alicia H. Jubert* and Eduardo L. Varetti** ...
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Glutathione S-transferases (GST, E.C.2.5.1.18) comprise a family of detoxification enzymes. Elevated levels of specific GST isozymes in tumor cells are thought responsible for resistance to chemotherapeutics, which renders selective GST... more
Glutathione S-transferases (GST, E.C.2.5.1.18) comprise a family of detoxification enzymes. Elevated levels of specific GST isozymes in tumor cells are thought responsible for resistance to chemotherapeutics, which renders selective GST inhibitors potentially useful pharmaceutical agents. We discuss the development of a structure activity model that rationalizes the isozyme selectivity observed in a series of 12 glutathione (GSH) analogues. Enzymatic activity data was determined for human P1-1, A1-1, and M2-2 isozymes, and these data were then considered in light of structural features of these three GST proteins. A survey of all GST structures in the PDB revealed that GSH binds to these proteins in a single "bioactive" conformation. To focus on differences between binding sites, we exploited our finding of a common GSH conformation and aligned the GST x-ray structures using bound ligands rather than the backbones of the different proteins. Once aligned, binding site lipophilicity and electrostatic potentials were computed, visualized, and compared. Docking and energy minimization exercises provided additional refinements to a model of selectivity developed initially by visual analysis. Our results suggest that binding site shape and lipophilic character are key determinants of GST isozyme selectivity for close GSH analogues.
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Glutathione S-transferases (GST) are a major class of phase II detoxifying enzymes that conjugate glutathione to electrophiles. Their involvement in the degradation of chemotherapeutic agents, which contributes to drug resistance, makes... more
Glutathione S-transferases (GST) are a major class of phase II detoxifying enzymes that conjugate glutathione to electrophiles. Their involvement in the degradation of chemotherapeutic agents, which contributes to drug resistance, makes this family of enzymes potential targets for therapeutic agents. This study generates, by homology modeling, a 3-D structure of three GST human isozymes of the Mu class, M1b-1b, M2-2 and M3-3, using the Rat3-3 GST structure as a template. The high percentage of identity among these enzymes and the lack of insertions and deletions make the system ideally suited to the technique of homology modeling. A novel technique for the modeling of protein structures was applied. The structure of the template was used to generate a low-resolution crystallographic map in which the initial coordinates of the structure to be modeled were placed. The structure was then annealed within this envelope. In addition, a feedback-restrained molecular dynamics procedure was adopted to scale the template restraints during the simulations. Three independent validation procedures were applied. To assess the reliability of the methods, an identical series of simulation steps to those used in the refinement were applied to the template structure (self modeling). Further, a homology structure for the Rat3-3 template was generated, starting from the modeled M1b-1b structure (reverse modeling). To assess the reasonableness of the modeled structures, two recently developed methodologies to verify protein structures based on statistics of the nonbonded interactions were applied. Overall, the structures appear to be consistent.
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Enzymes that utilize nicotinamide adenine dinucleotide (NAD) or its... more
Enzymes that utilize nicotinamide adenine dinucleotide (NAD) or its 2'-phosphate derivative (NADP) are found throughout the kingdoms of life. These enzymes are fundamental to many biochemical pathways, including central intermediary metabolism and mechanisms for cell survival and defense. The complete genomes of 25 organisms representing bacteria, protists, fungi, plants, and animals, and 811 viruses, were mined to identify and classify NAD(P)-dependent enzymes. An average of 3.4% of the proteins in these genomes was categorized as NAD(P)-utilizing proteins, with highest prevalence in the medium-chain oxidoreductase and short-chain oxidoreductase families. In general, the distribution of these enzymes by oxidoreductase family was correlated to the number of different catalytic mechanisms in each family. Organisms with smaller genomes encoded a larger proportion of NAD(P)-dependent enzymes in their proteome (approximately 6%) as compared to the larger genomes of eukaryotes (approximately 3%). Among viruses, those with large, double-strand DNA genomes were shown to encode oxidoreductases. Gram-positive and gram-negative bacteria showed some differences in the distribution of NAD(P)-dependent proteins. Several organisms such as M. tuberculosis, P. falciparum, and A. thaliana showed unique distributions of oxidoreductases corresponding to some phenotypic features.
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We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints... more
We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.