Discovery of Inhibitors of MDM2 Against Nasopharyngeal Cancer: An In-Silico Investigation

Abstract

Nasopharyngeal cancer is the fifth most common cancer among males in Malaysia between the ages of 25-59. Epstein-Barr virus is an established cause of nasopharyngeal cancer through an excess upregulation of Murine Double Minute 2 (MDM2). This study investigated potential lead candidates of MDM2 inhibitors by utilizing Molecular Docking and Molecular Dynamics Simulations with the existing drug database, DrugBank. Docking poses were predicted through GOLD molecular docking software utilizing GoldScore, ChemScore, and ChemPLP scoring functions; a consensus scoring was used, achieving an area under the receiver operating characteristic curve of 0.70. The top two compounds with high consensus docking scores, Venetoclax and Phaeophytin-B, were analyzed for binding stability through 250 ns of molecular dynamics simulation. Both Venetoclax and Phaeophytin-B showed good stability while posing favourable binding free energies of -50.46 kcal mol^-1 and -50.86 kcal mol^-1, respectively. Additionally, our MM‑GBSA calculations hinted that the interaction of Venetoclax and Phaeophytin-B with MDM2 is favoured through hydrophobic interactions – analogous to p53-MDM2 interactions. Our study proposes Venetoclax and Phaeophytin-B as potential chemical scaffolds that can be used for rational drug design of MDM2 inhibitors.