Insight into mechanism of small molecule inhibitors of the MDM2–p53 interaction: Molecular dynamics simulation and free energy analysis

Inhibition of the MDM2–p53 interaction is considered to be a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses were used to study the inhibitory mechanisms of four small molecule inhibitors, K23, YIN, DIZ and IMZ on the p53–MDM2 interaction. We found excellent agreement between the rank of the calculated absolute binding free energies using the MM-GBSA method and the experimentally determined rank. The results show that van der Waals energy is the dominant factor for the binding of the four inhibitors. Statistical analyses of the hydrophobic contacts between the inhibitors and MDM2 were performed, and the results suggested that these inhibitors form stable hydrophobic interactions with six residues of MDM2: Leu54, Gly58, Ile61, Met62, Val93 and His96. Calculations of the detailed van der Waals interactions between non-peptide inhibitors and individual protein residues can provide insights into the inhibitor-protein binding mechanism. Our studies suggest that the CH–π and π–π interactions between the four inhibitors and protein residues drive binding of the inhibitors in the hydrophobic cleft of MDM2.

Geometries of key residues, which produce some favorable interactions with the inhibitor IMZ is plotted in the complexes according to the lowest-energy structure from the MD trajectory.Figure optionsDownload high-quality image (135 K)Download as PowerPoint slideHighlights
► Statistical analyses of hydrophobic contacts suggest that the selected four inhibitors form stable hydrophobic interactions with six residues Leu54, Gly58, Ile61, Met62, Val93 and His96.
► Residue-based binding free energy decomposition analysis shows that the CH–π and π–π interactions between four inhibitors and residues drive the bindings of the inhibitors in hydrophobic cleft of MDM2.
► The calculation of binding free energy indicates that van der Waals interactions drive the bindings of the inhibitors K23, YIN, DIZ and IMZ to MDM2.