In silico High-Throughput Screening of ZINC Database of Natural Compounds to Identify Novel Histone Deacetylase Inhibitors

Abstract

Histone deacetylase 8 (HDAC8) is a zinc-binding metalloprotein being involved in transcriptional regulation, cell cycle progression and cellular development. Its overexpression is associated with various pathologies, including childhood neuroblastoma, leukemia, tumor progression and lung cancer. The FDA-approved HDAC inhibitors are not very safe due to various side effects. Therefore, we implemented an in silico high-throughput screening to identify novel HDAC8 inhibitors from the natural compounds database ([Formula: see text]) using computational methods. As a result, some drug-like substances ([Formula: see text]) with nontoxic profiles were identified as hit compounds after using molecular docking, including quantum polarized ligand and induced-fit docking approaches. One hit compound (ZINC02106564) was determined to be highly chemically reactive by using the DFT calculation. Finally, the top binder (ZINC12601598) to HDAC8 together with the reference inhibitor, was studied by 100[Formula: see text]ns molecular dynamics simulations, confirming previously obtained data. Overall, the proposed computational protocol might be prospective at the early stage of rational design for novel and less toxic HDAC8 inhibitors for the treatment of diverse diseases.