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Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV-1 protease by enhanced conformational sampling

文献类型：期刊论文

作者Chen, Jianzhong1,3; Peng, Cheng2,3; Wang, Jinan3; Zhu, Weiliang3
刊名PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
出版日期2018-12
卷号86期号:12页码:1294-1305
关键词allosteric inhibitor HIV-1 protease MM-GBSA normal mode analysis REMD
ISSN号0887-3585
DOI10.1002/prot.25610
文献子类Article
英文摘要Recently, allosteric regulations of HIV-1 protease (PR) are suggested as a promising approach to relieve drug resistance of mutations toward inhibitors targeting the active site of PR. Replica-exchange molecular dynamics (REMD) simulations and normal mode analysis (NMA) are integrated to enhance conformational sampling of PR. Molecular mechanics generalized Born surface area (MM-GBSA) method was applied to calculate binding free energies of three inhibitors APV, DRV, and NIT to the wild-type (WT) and multidrug resistance (MDR) PRs. The results suggest that binding free energies of APV and DRV are decreased in the MDR PR relative to the WT PR, suggesting drug resistance of mutations on these two inhibitors. However, the binding ability of the allosteric inhibitor NIT is not impaired in the MDR PR. In addition, internal dynamics analysis based on REMD simulations proves that mutations hardly produce obvious effect on the conformation of the MDR PR in comparison to the WT PR. Scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with residues of PRs on the concatenated trajectories of REMD demonstrates that mutations change the symmetric interaction networks of APV and DRV with PR, but do not generate obvious influence on the asymmetric interaction network of NIT with PR. In summary, allosteric inhibitor NIT can adapt the MDR PR better than those inhibitors toward the active site of PR, thus allosteric inhibitors of PR may be a possible channel to overcome drug resistance of PR.
WOS关键词NORMAL-MODE ANALYSIS ; DYNAMICS SIMULATIONS ; TRANSITION PATHWAY ; COMPLEX-FORMATION ; WILD-TYPE ; BINDING ; FLUCTUATIONS ; POLARIZATION ; FLEXIBILITY ; RECOGNITION
资助项目NSFC-Guangdong Joint Fund[U1501501] ; CAS Key Laboratory of Receptor Research[SIMM1706YKF-03] ; National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[11504206] ; National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[21403283] ; National Key Research and Development Program[2016YFA0502301]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics
语种英语
WOS记录号WOS:000453364400008
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/279473]  
专题药物发现与设计中心
通讯作者Chen, Jianzhong; Wang, Jinan; Zhu, Weiliang
作者单位1.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Shandong, Peoples R China;
2.Univ Chinese Acad Sci, Sch Chem, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Chen, Jianzhong,Peng, Cheng,Wang, Jinan,et al. Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV-1 protease by enhanced conformational sampling[J]. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS,2018,86(12):1294-1305.
APA Chen, Jianzhong,Peng, Cheng,Wang, Jinan,&Zhu, Weiliang.(2018).Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV-1 protease by enhanced conformational sampling.PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS,86(12),1294-1305.
MLA Chen, Jianzhong,et al."Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV-1 protease by enhanced conformational sampling".PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS 86.12(2018):1294-1305.

入库方式： OAI收割

来源：上海药物研究所

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