Document Detail

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations.
MedLine Citation:
PMID:  22408446     Owner:  NLM     Status:  PubMed-not-MEDLINE    
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 π-π, CH-π 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.
Jianzhong Chen; Dinglin Zhang; Yuxin Zhang; Guohui Li
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Publication Detail:
Type:  Journal Article     Date:  2012-02-17
Journal Detail:
Title:  International journal of molecular sciences     Volume:  13     ISSN:  1422-0067     ISO Abbreviation:  Int J Mol Sci     Publication Date:  2012  
Date Detail:
Created Date:  2012-03-12     Completed Date:  2012-10-02     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101092791     Medline TA:  Int J Mol Sci     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  2176-95     Citation Subset:  -    
Laboratory of Molecular Modeling and Design, State Kay Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116011, China; E-Mails: (J.C.); (D.Z.); (Y.Z.).
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