Discovery of Novel Inhibitors Targeting HDM2: Virtual Screening, Molecular Dynamics Simulation, Binding affinity predication and Cell Assay

Abstract HDM2(human double-minute 2 protein) is an important drug target for tumor treatment. The main physiological function of HDM2 is to negatively regulate the tumor suppressor protein p53 and inhibit the normal biological function of p53, which leads to the occurrence and development of tumors. Therefore, the discovery of small molecules that can inhibit the activity of HDM2 is a promising cancer therapy. In this study, we reported a virtual screening as an effective strategy to discover potential HDM2 inhibitors from the Specs database. Then 100 ns all-atom molecular dynamics (MD) simulation and binding free energies calculated were carried out on the selected compounds, and cell assay showed that Hit 3 was the most active against SMMC-7721 cell line with an IC50 of 14.14μM. In conclusion, we reported seven prospective candidates with novel skeletons among them Hit 3 is a potential HDM2 inhibitor and provided an insight into the mechanism of interaction of the compounds to HDM2 target.