Int. J. Mol. Sci. 2012, 13(2), 2176-2195; doi:10.3390/ijms13022176
Article

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

1 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 2 Department of Mathematics and Physics, Shandong Jiaotong University, Jinan 250031, China
* Author to whom correspondence should be addressed.
Received: 19 December 2011; in revised form: 4 January 2012 / Accepted: 9 January 2012 / Published: 17 February 2012
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Abstract: 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.
Keywords: p53-MDM2/MDMX interaction; molecular dynamics simulation; binding free energy; alanine scanning

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MDPI and ACS Style

Chen, J.; Zhang, D.; Zhang, Y.; Li, G. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations. Int. J. Mol. Sci. 2012, 13, 2176-2195.

AMA Style

Chen J, Zhang D, Zhang Y, Li G. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2012; 13(2):2176-2195.

Chicago/Turabian Style

Chen, Jianzhong; Zhang, Dinglin; Zhang, Yuxin; Li, Guohui. 2012. "Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations." Int. J. Mol. Sci. 13, no. 2: 2176-2195.

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