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

Received: 19 December 2011; in revised form: 4 January 2012 / Accepted: 9 January 2012 / Published: 17 February 2012
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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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