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题名: Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations
作者: Chen, Jianzhong1, 2;  Zhang, Dinglin1;  Zhang, Yuxin1;  Li, Guohui1
关键词: p53-MDM2/MDMX interaction ;  molecular dynamics simulation ;  binding free energy ;  alanine scanning
刊名: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
发表日期: 2012-02-01
DOI: 10.3390/ijms13022176
卷: 13, 期:2, 页:2176-2195
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD) simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA) method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the p-p, CH-p and CH-CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.
关键词[WOS]: PROTEIN-PROTEIN INTERACTIONS ;  FREE-ENERGY CALCULATIONS ;  GENERALIZED BORN MODEL ;  PARTICLE MESH EWALD ;  HIV-1 PROTEASE ;  MDM2 INHIBITORS ;  P53 RESTORATION ;  CANCER-THERAPY ;  STABILITY ;  DESIGN
语种: 英语
WOS记录号: WOS:000300715700057
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/143043
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.Shandong Jiaotong Univ, Dept Math & Phys, Jinan 250031, Peoples R China

Recommended Citation:
Chen, Jianzhong,Zhang, Dinglin,Zhang, Yuxin,et al. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2012,13(2):2176-2195.
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