A computational analysis of interaction mechanisms of peptide and non-peptide inhibitors with MDMX based on molecular dynamics simulation

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.