Probing Alterations in MDM2 Catalytic Core Structure Effect of Garcinia Mangostana Derivatives: Insight from Molecular Dynamics Simulations.

The MDM2-p53 protein-protein interaction is a promising model for researchers to design, study, and discover new anticancer drugs. The design of therapeutically active compounds that can maintain or restore the binding of MDM2 to p53 has been found to limit the oncogenic activities of both. This led to the current development of a group of xanthone-core and cis-imidazoline analogs compounds, among which γ-Mangostin (GM), α-Mangostin (AM), and Nutlin exhibited their MDM2-p53 interaction inhibitory effects. Therefore, in this study, we seek to determine the mechanisms by which these compounds elicit MDM2-p53 interaction targeting. Unique to the binding of GM, AM, and Nutlin, from our findings, they share the same three active site residues Val76, Tyr50, and Gly41, which represent the top active side residues that contribute to high electrostatic energy. Consequently, the free binding energy contributed enormously to the binding of these compounds, which culminated in the high binding affinities of GM, AM, and Nutlin with high values. Furthermore, GM, AM, and Nutlin commonly interrupted the stable and compact conformation of MDM2 coupled with its active site, where Cα deviations were relatively high. We believe that our findings would assist in the design of more potent active anticancer drugs.