Ligand-Based and Docking-Based Virtual Screening of MDM2 Inhibitors as Potent Anticancer Agents

Abstract

A ligand-based and docking-based virtual screening was carried out to identify novel MDM2 inhibitors. A pharmacophore model with four features was used for virtual screening, followed by molecular docking. Seventeen compounds were selected for an in vitro MDM2 inhibition assay, and compounds AO-476/43250177, AG-690/37072075, AK-968/15254441, AO-022/43452814, and AF-399/25108021 showed promising MDM2 inhibition activities with K _i values of 9.5, 8.5, 23.4, 3.2, and 23.1 μM, respectively. Four compounds also showed antiproliferative activity, and compound AO-022/43452814 was the most potent hit with IC₅₀ values of 19.35, 26.73, 12.63, and 24.14 μM against MCF7 (p53 +/+), MCF7 (p53 -/-), HCT116 (p53 +/+), and HCT116 (p53 -/-) cell lines, respectively. Compound AO-022/43452814 could be used as a scaffold for the development of anticancer agents targeting MDM2.