ArticlePLoS computational biology2014
P-loop conformation governed crizotinib resistance in G2032R-mutated ROS1 tyrosine kinase: clues from free energy landscape.
Article in PLoS computational biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 97 citations in OpenAlex.
- Article
- Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation.Research (Washington, D.C.) · 2023Article
- Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations.Nature protocols · 2022Review
- Binding Analysis Using Accelerated Molecular Dynamics Simulations and Future Perspectives.Advances and applications in bioinformatics and chemistry : AABC · 2022Review
- First Principles Calculation of Protein-Protein Dimer Affinities of ALS-Associated SOD1 Mutants.Frontiers in molecular biosciences · 2022Article
- Pharmacophore-based designing of putative ROS-1 targeting agents for NSCLC.Molecular diversity · 2021Article
- Importance of protein flexibility in ranking ERK2 Type IRSC advances · 2019Article
- Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers.PLoS computational biology · 2019Review
- Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type IFrontiers in pharmacology · 2019Article
- Gaussian accelerated molecular dynamics for elucidation of drug pathways.Expert opinion on drug discovery · 2018Review
- Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant CompoundCancer discovery · 2018Article
- Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation.International journal of molecular sciences · 2017Article
- Gaining insight into crizotinib resistance mechanisms caused by L2026M and G2032R mutations in ROS1 via molecular dynamics simulations and free-energy calculations.Journal of molecular modeling · 2017Article
- [Research Progress of Targeted Therapy for Anaplastic Lymphoma Kinase and Other Rare Driver Genes in Advanced Non-small Cell Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2017Review
- Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma.Expert review of molecular diagnostics · 2016Review
- Study on the Application of the Combination of TMD Simulation and Umbrella Sampling in PMF Calculation for Molecular Conformational Transitions.International journal of molecular sciences · 2016Article
- Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery.Scientific reports · 2016Article
- ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance.Oncotarget · 2016Review
- The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B.Scientific reports · 2016Article
- Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.PLoS computational biology · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tyrosine kinases are regarded as excellent targets for chemical drug therapy of carcinomas. However, under strong purifying selection, drug resistance usually occurs in the cancer cells within a short term. Many cases of drug resistance have been found to be associated with secondary mutations in drug target, which lead to the attenuated drug-target interactions. For example, recently, an acquired secondary mutation, G2032R, has been detected in the drug target, ROS1 tyrosine kinase, from a crizotinib-resistant patient, who responded poorly to crizotinib within a very short therapeutic term. It was supposed that the mutation was located at the solvent front and might hinder the drug binding. However, a different fact could be uncovered by the simulations reported in this study. Here, free energy surfaces were characterized by the drug-target distance and the phosphate-binding loop (P-loop) conformational change of the crizotinib-ROS1 complex through advanced molecular dynamics techniques, and it was revealed that the more rigid P-loop region in the G2032R-mutated ROS1 was primarily responsible for the crizotinib resistance, which on one hand, impaired the binding of crizotinib directly, and on the other hand, shortened the residence time induced by the flattened free energy surface. Therefore, both of the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the kinase resistance.
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