Quercetin and taxifolin completely break MDM2–p53 association: molecular dynamics simulation study

Inhibition of the MDM2–p53 interaction has been becomes a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations were used to study the effects of quercetin and taxifolin on MDM2–p53 complex. We found that binding of ligands (quercetin and taxifolin) led to the dissociation of MDM2–p53 complex. Analyses of the hydrophobic contacts between the inhibitors and MDM2–p53 were performed, and the results suggested that these ligands form stable hydrophobic interactions with MDM2 which led to complete disruption of MDM2–p53 hydrophobic interactions and dissociation of p53 from the complex. Our study suggests that the pi–pi stacking between Tyr 51 of MDM2 and aromatic rings of ligands is the critical event in MDM2–p53 dissociation.