Revealing Acquired Resistance Mechanisms of Kinase-Targeted Drugs Using an on-the-Fly, Function-Site Interaction Fingerprint Approach
- Zheng Zhao
Zheng ZhaoDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United StatesMore by Zheng Zhao
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- Philip E. Bourne*
Philip E. Bourne*Email: : [email protected]Department of Biomedical Engineering and School of Data Science, University of Virginia, Charlottesville, Virginia 22904, United StatesMore by Philip E. Bourne
Abstract
Although kinase-targeted drugs have achieved significant clinical success, they are frequently subject to the limitations of drug resistance, which has become a primary vulnerability to targeted drug therapy. Therefore, deciphering resistance mechanisms is an important step in designing more efficacious, antiresistant drugs. Here we studied two FDA-approved kinase drugs: Crizotinib and Ceritinib, which are first- and second-generation anaplastic lymphoma kinase (ALK) targeted inhibitors, to unravel drug-resistance mechanisms. We used an on-the-fly, function-site interaction fingerprint (on-the-fly Fs-IFP) approach, combining binding free-energy surface calculations with the Fs-IFPs. Establishing the potentials of mean force and monitoring the atomic-scale protein–ligand interactions, before and after L1196M-induced drug resistance, revealed insights into drug-resistance/antiresistant mechanisms. Crizotinib prefers to bind the wild-type ALK kinase domain, whereas Ceritinib binds more favorably to the mutated ALK kinase domain, in agreement with experimental results. We determined that ALK kinase–drug interactions in the region of the front pocket are associated with drug resistance. Additionally, we find that the L1196M mutation does not simply alter the binding modes of inhibitors but also affects the flexibility of the entire ALK kinase domain. Our work provides an understanding of the mechanisms of ALK drug resistance, confirms the usefulness of the on-the-fly Fs-IFP approach, and provides a practical paradigm to study drug-resistance mechanisms in prospective drug discovery.
Cited By
This article is cited by 6 publications.
- Zheng Zhao, Philip E. Bourne. Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors. ACS Pharmacology & Translational Science 2023, 6 (8) , 1182-1191. https://doi.org/10.1021/acsptsci.3c00078
- Zheng Zhao, Niraja Bohidar, Philip E. Bourne. Analysis of KRAS–Ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics. Journal of Chemical Information and Modeling 2023, 63 (4) , 1362-1370. https://doi.org/10.1021/acs.jcim.3c00097
- Zheng Zhao, Philip E. Bourne. Structural Insights into the Binding Modes of Viral RNA-Dependent RNA Polymerases Using a Function-Site Interaction Fingerprint Method for RNA Virus Drug Discovery. Journal of Proteome Research 2020, 19 (11) , 4698-4705. https://doi.org/10.1021/acs.jproteome.0c00623
- Zheng Zhao, Philip E. Bourne. Harnessing systematic protein–ligand interaction fingerprints for drug discovery. Drug Discovery Today 2022, 27 (10) , 103319. https://doi.org/10.1016/j.drudis.2022.07.004
- Zheng Zhao, Philip E. Bourne. Using the Structural Kinome to Systematize Kinase Drug Discovery. 2021https://doi.org/10.5772/intechopen.100109
- Javier Vázquez, Manel López, Enric Gibert, Enric Herrero, F. Javier Luque. Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches. Molecules 2020, 25 (20) , 4723. https://doi.org/10.3390/molecules25204723