Exploring the efficacy of naturally occurring C-C and C-O-C type biflavonoids towards the inhibition of MDM2-p53 interactions

Abstract

Abstract P53-MDM2 protein-protein interaction (PPI) is one of the most well-established studied which is involved in human cancer. Most importantly, cell cycle and apoptosis are potentially regulated by the p53 protein. Minute double minute 2 (MDM2), the negative regulator of p53, induces p53 degradation and modulates its tumour-suppressing activity. Regaining p53 function by targeting and inhibiting the p53-MDM2 interaction for the treatment of cancer is a unique approach. In this present study, three C-C type biflavonoids (amentoflavone, robustaflavone and agathisflavone) and three C-O-C type biflavonoids (ochnaflavone, hinokiflavone and delicaflavone) were used as MDM2 inhibitors. Molecular docking and molecular dynamics (MD) simulation studies were done to show the p53-MDM2 inhibitory effect of six naturally occurring biflavonoid-based small molecules and determined the various possible conformations and binding affinity values and investigated the dynamic behaviour of MDM2-biflavonoid complexes. Both the C-C and C-O-C category of biflavonoids potentially inhibit p53-MDM2 interaction by blocking the p53-binding domain of MDM2. From the docking score, one of the C-C type biflavonoid, amentoflavone was found to be the strongest inhibitor i.e., strong binding affinity compared to the reference compound nutlin-3 towards MDM2 protein. MD simulation study showed similar RMSD, RMSF, RoG, and SASA profiles compared to the reference inhibitor nutlin-3, suggesting stability throughout the simulation time. These results indicate naturally occurring biflavonoids might be promising early lead compounds for the development of new anticancer agents targeting p53-MDM2 interaction, which to our knowledge has never been reported to disrupt p53-MDM2 interaction.