The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and in vitro/in vivo Biological Evaluation

Abstract

Small-molecule inhibitors of MDM2 that block the MDM2-p53 protein-protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1-5) that display significant inhibitory effects on MDM2-p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY-5 is the most active MDM2 inhibitor with an IC₅₀ value of 14.1±2.8 nM. Moreover, WY-5 significantly up-regulate the protein level of p53 in SK-Hep-1 cells harboring wild-type p53. In vitro anticancer study reveals that WY-5 markedly inhibits the survival of SK-Hep-1 cells. In vivo anticancer study suggests that WY-5 significantly inhibits the growth of SK-Hep-1 cells-derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY-5 may be a promising candidate for the treatment of cancer harboring wild-type p53.

Keywords: MDM2; cancer treatment; molecular docking; p53; virtual screening.