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题名: Computational study on the drug resistance mechanism of hepatitis C virus NS5B RNA-dependent RNA polymerase mutants to BMS-791325 by molecular dynamics simulation and binding free energy calculations
作者: Pan, DB; Niu, YZ; Xue, WW; Bai, QF; Liu, HX; Yao, XJ(姚小军)
收录类别: SCIE ; CPCI-S
出版日期: 2016-05-15
会议名称: 15th Conference on Chemometrics in Analytical Chemistry
会议日期: JUN 22-26, 2015
会议地点: Changsha, PEOPLES R CHINA
英文摘要: Hepatitis C Virus (HCV) NS5B RNA-dependent RNA polymerase is an attractive target for anti-HCV development. Several mutations such as A421V, 13921 and P495L in thumb'I pocket of HCV NS5B polymerase have been proved to be resistant to BMS-791325 (Phase III clinical trial). A deep understanding of the resistance mechanism conferred by these mutations is important to the design and discovery of more new effective drugs against resistant HCV strains. We performed molecular dynamics (MD) simulations, free energy calculation and adaptive biasing force (ABF) simulation to study the possible resistance mechanism conferred by the above mutants. MD simulation results show the hydrophobic interaction is the driving force for BMS-791325 binding. ABF simulation proves that attenuation of the hydrophilic interaction between R503 and BMS-791325 is the first step for drug to escape from the binding site. Loss of the hydrophilic interaction makes drug easily to move out of the hydrophobic pocket. The simulation results further reveal that A421V, L392I and P495L mutants reduce drug binding affinity. P495L mutant makes the binding pocket more flexible and cannot anchor BMS-791325. The altered hydrophilic interactions of mutant residues are the essential reasons leading to drug resistance in A421V and L392I mutants. Our results will provide useful information to develop effective HCV NS5B inhibitors against resistance. (C) 2016 Elsevier B.V. All rights reserved.
关键词: Drug resistance mechanism ; Hepatitis C Virus NS5B RNA-dependent ; RNA polymerase ; BMS-791325 ; Molecular dynamics simulation ; Binding free energy calculations
作者部门: [Pan, Dabo ; Niu, Yuzhen ; Xue, Weiwei ; Bai, Qifeng ; Yao, Xiaojun] Lanzhou Univ, Dept Chem, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China ; [Liu, Huanxiang] Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China ; [Yao, Xiaojun] Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
通讯作者: Yao, XJ (reprint author), Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China.
学科分类: Automation & Control Systems; Chemistry; Computer Science; Instruments & Instrumentation; Mathematics
会议录: CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS
卷号: 154
页码: 185-193
出版者: Elsevier
出版地: AMSTERDAM
语种: 英语
DOI: 10.1016/j.chemolab.2016.03.015
ISSN号: 0169-7439
WOS记录号: WOS:000376547600020
IR记录号: WOS:000376547600020
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内容类型: 会议论文
URI标识: http://ir.lzu.edu.cn/handle/262010/185203
Appears in Collections:化学化工学院_会议论文

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Recommended Citation:
Pan, DB,Niu, YZ,Xue, WW,et al. Computational study on the drug resistance mechanism of hepatitis C virus NS5B RNA-dependent RNA polymerase mutants to BMS-791325 by molecular dynamics simulation and binding free energy calculations[C]. 见:15th Conference on Chemometrics in Analytical Chemistry. Changsha, PEOPLES R CHINA. JUN 22-26, 2015.
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