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Insight into mechanism of small molecule inhibitors of the MDM2-p53 interaction: Molecular dynamics simulation and free energy analysis
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
2011-09-01
DOI10.1016/j.jmgm.2011.06.003
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
关键词[WOS]PROTEIN-PROTEIN INTERACTION ; CANCER-THERAPY ; P53-MDM2 INTERACTION ; DRUG DISCOVERY ; IN-VIVO ; MM-PBSA ; BINDING ; P53 ; COMPLEX ; DESIGN
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.
语种英语
WOS记录号WOS:000297093600007
引用统计
被引频次:26[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/142604
专题中国科学院大连化学物理研究所
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
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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.
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