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

doi:10.1039/c8ra05042b

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations
	Chen, Jianzhong 1,2; Wang, Jinan 1; Lai, Fengbo 2; Wang, Wei 2; Pang, Laixue 2; Zhu, Weiliang1
刊名	RSC ADVANCES
	2018
卷号	8 期号:45 页码:25456-25467
ISSN号	2046-2069
DOI	10.1039/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.
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关键词	HSP90 MOLECULAR CHAPERONE ; FREE-ENERGY CALCULATIONS ; HIV-1 PROTEASE ; COMPUTATIONAL ANALYSIS ; LIGAND INTERACTIONS ; DRUG-RESISTANCE ; PK(A) VALUES ; CANCER ; SIMULATION ; DISCOVERY
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000439323300024
内容类型	期刊论文
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.