期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 13, 期 2, 页码 2176-2195出版社
MDPI
DOI: 10.3390/ijms13022176
关键词
p53-MDM2/MDMX interaction; molecular dynamics simulation; binding free energy; alanine scanning
资金
- National High-tech Research and Development Program [2009AA01A137]
- National Natural Science Foundation of China [31070641/C050101]
- Chinese Academy Sciences
- Dr. Start-up Foundation for Shandong Jiaotong University
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据