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Title: A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK

Abstract

Highlights: Black-Right-Pointing-Pointer The study revealed the detailed resistance mechanism of the non-active mutation C1156Y in ALK. Black-Right-Pointing-Pointer C1156Y leads to crizotinib displacement and conformational changes in the binding cavity. Black-Right-Pointing-Pointer The conformations cause a decline in the vdW and electrostatic energy between crizotinib and ALK. -- Abstract: Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may givemore » a vital clue for the design of drugs to combat crizotinib resistance.« less

Authors:
 [1];  [2];  [3]
  1. Shandong University of Technology, Zibo 255049 (China)
  2. National Key Laboratory of Crop Genetic Improvement, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China)
  3. (China)
Publication Date:
OSTI Identifier:
22207917
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 423; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; CONFORMATIONAL CHANGES; DISLOCATIONS; DRUGS; LUNGS; LYMPHOMAS; MOLECULAR DYNAMICS METHOD; MUTATIONS; VAN DER WAALS FORCES

Citation Formats

Sun, Hui-Yong, Ji, Feng-Qin, E-mail: fengqinji@mail.hzau.edu.cn, and Center for Bioinformatics, Huazhong Agricultural University, Wuhan 430070. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.05.120.
Sun, Hui-Yong, Ji, Feng-Qin, E-mail: fengqinji@mail.hzau.edu.cn, & Center for Bioinformatics, Huazhong Agricultural University, Wuhan 430070. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK. United States. doi:10.1016/J.BBRC.2012.05.120.
Sun, Hui-Yong, Ji, Feng-Qin, E-mail: fengqinji@mail.hzau.edu.cn, and Center for Bioinformatics, Huazhong Agricultural University, Wuhan 430070. Fri . "A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK". United States. doi:10.1016/J.BBRC.2012.05.120.
@article{osti_22207917,
title = {A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK},
author = {Sun, Hui-Yong and Ji, Feng-Qin, E-mail: fengqinji@mail.hzau.edu.cn and Center for Bioinformatics, Huazhong Agricultural University, Wuhan 430070},
abstractNote = {Highlights: Black-Right-Pointing-Pointer The study revealed the detailed resistance mechanism of the non-active mutation C1156Y in ALK. Black-Right-Pointing-Pointer C1156Y leads to crizotinib displacement and conformational changes in the binding cavity. Black-Right-Pointing-Pointer The conformations cause a decline in the vdW and electrostatic energy between crizotinib and ALK. -- Abstract: Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.},
doi = {10.1016/J.BBRC.2012.05.120},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 423,
place = {United States},
year = {2012},
month = {6}
}