Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis

doi:10.1016/j.jmgm.2011.06.003

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	Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis
	Chen, Jianzhong 2,3; Wang, Jinan 1; Xu, Beisi 3; Zhu, Weiliang1 ; Li, Guohui 3
刊名	JOURNAL OF MOLECULAR GRAPHICS & MODELLING
	2011-09
卷号	30 页码:46-53
关键词	MDM2-p53 interaction Cross-correlation analysis Molecular dynamics simulation Binding free energy Hydrophobic interaction
ISSN号	1093-3263
DOI	10.1016/j.jmgm.2011.06.003
文献子类	Article
英文摘要	Inhibition of the MDM2-p53 interaction is considered to be a new therapeutic strategy to activate wildtype p53 in tumors. Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses were used to study the inhibitory mechanisms of four small molecule inhibitors, K23, YIN, DIZ and IMZ on the p53-MDM2 interaction. We found excellent agreement between the rank of the calculated absolute binding free energies using the MM-GBSA method and the experimentally determined rank. The results show that van der Waals energy is the dominant factor for the binding of the four inhibitors. Statistical analyses of the hydrophobic contacts between the inhibitors and MDM2 were performed, and the results suggested that these inhibitors form stable hydrophobic interactions with six residues of MDM2: Leu54, Gly58,IIe61, Met62, Val93 and His96. Calculations of the detailed van der Waals interactions between non-peptide inhibitors and individual protein residues can provide insights into the inhibitor-protein binding mechanism. Our studies suggest that the CH-pi and pi-pi interactions between the four inhibitors and protein residues drive binding of the inhibitors in the hydrophobic cleft of MDM2. (C) 2011 Elsevier Inc. All rights reserved.
资助项目	National High-tech Research and Development Program[2009AA01A137] ; National Natural Science Foundation of China[31070641/C050101] ; Chinese Academy Sciences[00000000]
WOS关键词	PROTEIN-PROTEIN INTERACTION ; CANCER-THERAPY ; P53-MDM2 INTERACTION ; DRUG DISCOVERY ; IN-VIVO ; MM-PBSA ; BINDING ; P53 ; COMPLEX ; DESIGN
WOS研究方向	Biochemistry & Molecular Biology ; Computer Science ; Crystallography ; Mathematical & Computational Biology
语种	英语
出版者	ELSEVIER SCIENCE INC
WOS记录号	WOS:000297093600007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278411]
专题	药物发现与设计中心
通讯作者	Li, Guohui
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Shanghai Jiao Tong Univ, Dept Math & Phys, Jinan 250031, Peoples R China; 3.Chinese Acad Sci, Dalian Inst Chem Phys, State Kay Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116011, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Jianzhong,Wang, Jinan,Xu, Beisi,et al. Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2011,30:46-53.
APA	Chen, Jianzhong,Wang, Jinan,Xu, Beisi,Zhu, Weiliang,&Li, Guohui.(2011).Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis.JOURNAL OF MOLECULAR GRAPHICS & MODELLING,30,46-53.
MLA	Chen, Jianzhong,et al."Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis".JOURNAL OF MOLECULAR GRAPHICS & MODELLING 30(2011):46-53.