Insight into the interaction mechanism of inhibitors P4 and WK23 with MDM2 based on molecular dynamics simulation and different free energy methods

The p53–MDM2 interaction has been an important target for the designs of anticancer drugs. In this work, molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) methods were applied to calculate binding free energies of MDM2 with the peptide inhibitor P4 and non-peptide inhibitor WK23. The binding free energies predicted by two different free energy methods agree well with the experimental values. The results suggest that van der Waals interaction is the main force of inhibitor bindings to MDM2. Dynamics analysis and the inhibitor–residue interactions were also performed. The results show that the CH–CH, CH–π and π–π interactions drive the bindings of inhibitors to MDM2 and the peptide inhibitor P4 can produce strong interactions with more residues of MDM2 than WK23. We expect that this study can provide important helps for the designs of potent inhibitors targeting the p53–MDM2 interactions.