ArticleResearch (Washington, D.C.)2023
Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation.
Article in Research (Washington, D.C.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
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- Drug Resistance Predictions Based on a Directed Flag Transformer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Identifying Inhibitor-SARS-CoV2-3CLMolecules (Basel, Switzerland) · 2025Article
- Molecular docking and dynamics in protein serine/threonine kinase drug discovery: advances, challenges, and future perspectives.Frontiers in pharmacology · 2025Review
- Discovery of a Novel Selective PAK1/HDAC6/HDAC10 Inhibitor ZMF-25 that Induces Mitochondrial Metabolic Breakdown and Autophagy-Related Cell Death in Triple-Negative Breast Cancer.Research (Washington, D.C.) · 2025Article
- Discovery of Novel NaResearch (Washington, D.C.) · 2025Article
- Molecular Merged Hypergraph Neural Network for Explainable Solvation Gibbs Free Energy Prediction.Research (Washington, D.C.) · 2025Article
- Identification of mIDH1 R132C/S280F Inhibitors from Natural Products by Integrated Molecular Docking, Pharmacophore Modeling and Molecular Dynamics Simulations.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Unraveling Extremely DamagingJournal of personalized medicine · 2023Article
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Authors and funding
9 authors.
Funding
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Abstract
Anaplastic lymphoma kinase (ALK), a tyrosine receptor kinase, has been proven to be associated with the occurrence of numerous malignancies. Although there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials, the occurrence of various mutations seriously attenuates the effectiveness of the drugs. Unfortunately, most of the drug resistance mechanisms still remain obscure. Therefore, it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the mutations. In this work, on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies [end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area (MM/PB(GB)SA) and alchemical method of Thermodynamic Integration (TI)], we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms, covering the one-drug-multiple-mutation and multiple-drug-one-mutation cases. Through conventional molecular dynamics (cMD) simulation in conjunction with MM/PB(GB)SA and umbrella sampling (US) in conjunction with contact network analysis (CNA), the resistance mechanisms of the in-pocket, out-pocket, and multiple-site mutations were revealed. Especially for the out-pocket mutation, a possible transfer chain of the mutation effect was revealed, and the reason why different drugs exhibited various sensitivities to the same mutation was also uncovered. The proposed mechanisms may be prevalent in various drug resistance cases.
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Registered trials
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