Identifying Potential p53‐MDM2 Interaction Antagonists: An Integrated Approach of Pharmacophore‐Based Virtual Screening, Interaction Fingerprinting, MD Simulation and DFT Studies

Abstract

AbstractThe inactivation of p53 in tumor cells is as a result of the deletion or mutation of the TP3 gene, while the inhibition of its activity is by interaction with overexpressed mouse double minute 2 (MDM2). Small‐molecule inhibitors that target the interaction between p53 and MDM2 are now being pursued as potential therapeutic agents for cancer therapy. To date, many small‐molecule inhibitors of the p53‐MDM2 interaction have been identified which, however, possess toxicity, bioavailability and/or drug resistance limitations. In this study, we directed a ligand‐based pharmacophore modeling protocol towards the search of novel inhibitors of the p53‐MDM2 interaction. Generated pharmacophore features from known and novel inhibitors of the p53‐MDM2 interaction were used in searching the ZINC database for drug‐like molecules. With stringent search parameters set, we generated a ligand library of 7000 ZINC compounds and a sub‐library of 907 compounds from the Selleckchem's “Apoptosis Compound Library”. Upon the docking of both compound libraries to the target receptor, the resulting top 100 binders were subjected to in silico ADMET screening, out of which the top 3 compounds with the most favorable properties (ZINC71932671, ZINC02375540 and ZINC08870467) were selected for further assessment. These 3 hits also displayed favorable interactions with important residues involved in the p53‐MDM2 protein‐protein interaction, while the molecular dynamics simulation study suggest a stable conformation for the protein‐ligand complexes. These three compounds can be used in the development of potential cancer therapeutics that are targeted at restoring the function of p53 by blocking its interaction with MDM2.