A computational analysis of interaction mechanisms of peptide and non-peptide inhibitors with MDMX based on molecular dynamics simulation
A computational analysis of interaction mechanisms of peptide and non-peptide inhibitors with MDMX based on molecular dynamics simulation
复制标题
基于分子动力学模拟的肽类和非肽类抑制剂与MDMX相互作用机制的计算分析
DOI：
10.1016/j.comptc.2012.01.010
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发表时间：
2012-03-15
影响因子：
2.8
通讯作者：
Wang, Ke-yan
中科院分区：
文献类型：
--
作者：
Cheng, Wei-yuan;Chen, Jian-zhong;Wang, Ke-yan
抑制P53-MDM2/MDMX相互作用被认为是在肿瘤中激活野生型P53的新途径。采用分子动力学模拟(MD)和分子力学广义玻恩表面积(MM-GBSA)相结合的方法，探讨了多肽和非肽类药物与MDMX的结合机理。结果表明，范德华能是缓蚀剂与MDMX结合的主要作用力。我们发现，多肽抑制剂与MDMX的相互作用应该比非多肽抑制剂多。通过计算丙氨酸扫描和结构亲和关系分析来预测抑制物与蛋白质的结合模式。结果表明，6种常见残基Met53、Ile60、Met61、Tyr66、Val92和Leu98位于缓蚀剂与MDMX之间的表面热点。动力学性质分析表明，这些多肽抑制剂有利于抑制剂-MDMX络合物的稳定性。我们期望这项研究能够对针对P53-MDMX相互作用的有效抑制剂的设计做出重要贡献。(C)2012爱思唯尔B.V.保留所有权利。
Inhibition of p53-MDM2/MDMX interaction is considered to be a new approach to active wild type p53 in tumors. Molecular dynamics simulation (MD) coupled with molecular mechanics generalized Born surface area (MM-GBSA) method were performed to probe the binding mechanisms of peptide and non-peptide inhibitors to MDMX. The results show that van der Waals energy is a main force of the inhibitor-MDMX binding. We found that the peptide inhibitors should generate more interaction contacts with MDMX than the non-peptide inhibitors. Computational alanine scanning and analysis of structure-affinity relation were used to predict the inhibitor-protein binding modes. The results show that six common residues Met53, Ile60, Met61, Tyr66, Val92 and Leu98 locate in the hot spot of the surface between inhibitors and MDMX. The analyses of dynamics properties suggest that the peptide inhibitors are in favor of the stability of the inhibitor-MDMX complex. We expect that this study can contribute significantly to the designs of the potent inhibitors targeting the p53-MDMX interaction. (C) 2012 Elsevier B.V. All rights reserved.