title: P-loop conformation governed crizotinib resistance in G2032R-mutated ROS1 tyrosine kinase: clues from free energy landscape.
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.
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM) and Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics*; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human