Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration

doi:10.1111/cbdd.13345

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	Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration
	Chen, Jianzhong 1,2; Wang, Jinan 2; Pang, Laixue 1; Zhu, Weiliang2
刊名	CHEMICAL BIOLOGY & DRUG DESIGN
	2018-10
卷号	92 期号:4 页码:1763-1777
关键词	hydrophobic contact scanning MM-GBSA p53-MDM2 interaction principal component analysis solvated interaction energy
ISSN号	1747-0277
DOI	10.1111/cbdd.13345
文献子类	Article
英文摘要	Disruption of the p53-MDM2 interaction has been an efficient strategy to renew the function of wild-type p53. In this work, molecular dynamic simulations, molecular mechanics-generalized Born surface area method, and principal component analysis were combined to probe interaction mechanism of inhibitors 2TZ, 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2. The rank of our current predicted binding free energies is in agreement with that of the experimental values. The results demonstrate that the introductions of thiazole and pyridine rings into 2TZ as well as the change in the orientation of inhibitors lead to the increase in the polar interactions of 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2 relative to 2TZ. The information derived from principal component analysis suggests that inhibitor bindings produce significant effect on the binding cleft of MDM2 and make the binding cleft wider and bigger so as to accommodate different type inhibitors. This study is looked forward to contributing theoretical hints for designs of potent inhibitors targeting the p53-MDM2 interaction.
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[81273435] ; National Natural Science Foundation of China[81573350] ; Shandong Province Key Research and Development Program[2016GGX102043] ; CAS Key Laboratory of Receptor Research[SIMM1706YKF-03] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501]
WOS关键词	PROTEIN-PROTEIN INTERACTIONS ; SOLVATED INTERACTION ENERGY ; BOUNDARY-ELEMENT METHOD ; STRUCTURE-BASED DESIGN ; BINDING FREE-ENERGIES ; PARTICLE MESH EWALD ; CONFORMATIONAL-CHANGES ; MDM2-MEDIATED UBIQUITINATION ; PEPTIDE INHIBITION ; P53 MUTATIONS
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000452242200005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279544]
专题	药物发现与设计中心
通讯作者	Chen, Jianzhong; Wang, Jinan; Pang, Laixue
作者单位	1.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Shandong, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chen, Jianzhong,Wang, Jinan,Pang, Laixue,et al. Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2018,92(4):1763-1777.
APA	Chen, Jianzhong,Wang, Jinan,Pang, Laixue,&Zhu, Weiliang.(2018).Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration.CHEMICAL BIOLOGY & DRUG DESIGN,92(4),1763-1777.
MLA	Chen, Jianzhong,et al."Inhibiting mechanism of small molecule toward the p53-MDM2 interaction: A molecular dynamic exploration".CHEMICAL BIOLOGY & DRUG DESIGN 92.4(2018):1763-1777.