Discovery of potent HDAC2 inhibitors based on virtual screening in combination with drug repurposing

Histone deacetylase 2 (HDAC2) is a vital therapeutic target for cancer and neurodegenerative diseases. Although some highly effective HDAC2 inhibitors were developed, their serious side effects and toxicity have not been well resolved. Currently, drug repurposing has been an efficient strategy in drug discovery. In this study, a series of in silico simulations and drug repurposing approaches were employed to identify promising HDAC2 inhibitors. We first constructed a receptor-ligand pharmacophore model. Notably, we combined pharmacophore model construction with molecular dynamics simulation, and used dynamic interatomic distances to evaluate the stability of the interactions and the importance of features in pharmacophore. In addition, molecular docking and molecular dynamics simulations were used to perform further screening. The results suggested that compounds DB08464, DB00731 (Nateglinide), DB13930 (Ulixertinib) and DB13696 (Salifungin) stably bound to HDAC2 and produced many favorable interactions. The MTT assay pointed out that one of the screened compounds, the antiviral drug DB13696, showed obvious anti-proliferative ability on HepG2 cells with high HDAC2 expression, indicating that the calculated methods performed in this study should be reliable.