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题名: Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis
作者: Chen, Jianzhong1, 2;  Wang, Jinan3;  Xu, Beisi1;  Zhu, Weiliang3;  Li, Guohui1
关键词: MDM2-p53 interaction ;  Cross-correlation analysis ;  Molecular dynamics simulation ;  Binding free energy ;  Hydrophobic interaction
刊名: JOURNAL OF MOLECULAR GRAPHICS & MODELLING
发表日期: 2011-09-01
DOI: 10.1016/j.jmgm.2011.06.003
卷: 30, 页:46-53
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine ;  Technology ;  Physical Sciences
类目[WOS]: Biochemical Research Methods ;  Biochemistry & Molecular Biology ;  Computer Science, Interdisciplinary Applications ;  Crystallography ;  Mathematical & Computational Biology
研究领域[WOS]: Biochemistry & Molecular Biology ;  Computer Science ;  Crystallography ;  Mathematical & Computational Biology
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.
关键词[WOS]: PROTEIN-PROTEIN INTERACTION ;  CANCER-THERAPY ;  P53-MDM2 INTERACTION ;  DRUG DISCOVERY ;  IN-VIVO ;  MM-PBSA ;  BINDING ;  P53 ;  COMPLEX ;  DESIGN
语种: 英语
WOS记录号: WOS:000297093600007
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142604
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, State Kay Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116011, Peoples R China
2.Shanghai Jiao Tong Univ, Dept Math & Phys, Jinan 250031, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

Recommended Citation:
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.
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