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Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations

文献类型：期刊论文

作者Chen, Jianzhong1,2; Wang, Jinan1; Lai, Fengbo2; Wang, Wei2; Pang, Laixue2; Zhu, Weiliang1
刊名RSC ADVANCES
出版日期2018
卷号8期号:45页码:25456-25467
ISSN号2046-2069
DOI10.1039/c8ra05042b
文献子类Article
英文摘要Heat shock protein 90 (Hsp90) has been an attractive target of potential drug design for antitumor treatment. The current work integrates molecular dynamics (MD) simulations, calculations of binding free energy, and principal component (PC) analysis with scanning of inhibitor-residue interaction to probe the binding modes of inhibitors YK9, YKJ and YKI to Hsp90 and identify the hot spot of the inhibitor-Hsp90 binding. The results suggest that the introductions of two groups G1 and G2 into YKJ and YKI strengthen the binding ability of YKJ and YKI to Hsp90 compared to YK9. PC analysis based MD trajectories prove that inhibitor bindings exert significant effects on the conformational changes, internal dynamics and motion modes of Hsp90, especially for the helix 2 and the loops L1 and L2. The calculations of residue-based free energy decomposition and scanning of the inhibitor-Hsp90 interaction suggest that six residues L107, G108, F138, Y139, W162 and F170 construct the common hot spot of the inhibitor-residue interactions. Moreover the substitutions of the groups G1 and G2 in YKJ and YKI lead to two additional hydrogen bonding interactions and multiple hydrophobic interactions for bindings of YKJ and YKI to Hsp90. This work is also expected to contribute theoretical hints for the design of potent inhibitors toward Hsp90.
WOS关键词HSP90 MOLECULAR CHAPERONE ; FREE-ENERGY CALCULATIONS ; HIV-1 PROTEASE ; COMPUTATIONAL ANALYSIS ; LIGAND INTERACTIONS ; DRUG-RESISTANCE ; PK(A) VALUES ; CANCER ; SIMULATION ; DISCOVERY
资助项目National Key Research and Development Program[2016YFA0502301] ; National Natural Science Foundation of China[21403283] ; National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[11504206] ; National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[81573350] ; Shandong Province Key Research and Development Program[2016GGX102043] ; Shandong Provincial Natural Science Foundation[ZR2017MA040] ; Shandong Provincial Natural Science Foundation[ZR2015AL022] ; Project of Shandong Province Higher Educational Science and Technology Program[J18KA040] ; Project of Shandong Province Higher Educational Science and Technology Program[J17KA045] ; major development project of Shandong Jiaotong University[00000000] ; CAS Key Laboratory of Receptor Research[SIMM1706YKF-03]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000439323300024
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/272306]  
专题药物发现与设计中心
通讯作者Chen, Jianzhong; Pang, Laixue; Zhu, Weiliang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Shandong, Peoples R China;
推荐引用方式
GB/T 7714		 Chen, Jianzhong,Wang, Jinan,Lai, Fengbo,et al. Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations[J]. RSC ADVANCES,2018,8(45):25456-25467.
APA Chen, Jianzhong,Wang, Jinan,Lai, Fengbo,Wang, Wei,Pang, Laixue,&Zhu, Weiliang.(2018).Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations.RSC ADVANCES,8(45),25456-25467.
MLA Chen, Jianzhong,et al."Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations".RSC ADVANCES 8.45(2018):25456-25467.

入库方式： OAI收割

来源：上海药物研究所

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