Quercetin and taxifolin completely break MDM2-p53 association: Molecular dynamics simulation study

Abstract

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. © 2012 Springer Science+Business Media New York.