Structure based virtual screening, docking and molecular dynamic simulation studies to identify potent mdm2-p53 inhibitors: Future implications for cancer therapy

Abstract

Objective: To identify the p53 binding pocket as well as active residues in mdm2 protein, and search for similar (or) better compounds to inhibit mdm2-p53 interactions in comparison to FDA approved drug (Nutlin) by ligand and structure based virtual screening methods, docking, and molecular dynamic simulation studies. Methods: A structure and ligand based virtual screening for mdm2 protein; targeting the key residues involved in their active binding of p53 peptide was conducted after obtaining structurally suitable compounds similar to Nutlin from ZINC database. These compounds are virtually screened onto the mdm2 protein targeting its active binding site where p53 binds. The best compound with highest binding affinity was taken up for further analysis using molecular dynamic simulations for further validating the docking studies and to reveal interactions during the conformational changes Results: We discovered several compounds that are potentially able to block the interaction between active residues of mdm2 and p53 complex, suggesting their capability to act as anti-cancer agents. As proven by our structure based virtual screening studies coupled with semi-flexible and flexible docking studies, compound ZINC59256947 was found to be the strongest inhibitors for mdm2 protein amongst all of those isolates from ZINC database. Conclusion: Our results suggest that, a simple, selective and reliable inhibition assay can be performed to search for novel inhibitors of p53-mdm2 interaction. Therefore this study provides a rationalization to the ability of a ZINC59256947, an isolate from ZINC database with strong binding affinity towards mdm2 protein, for future implications as anti-cancer agent.