Discovery of Potential Selective HDAC8 Binders: Using Combination of Pharmacophore‐Based–Structure‐Based Virtual Screening, ADME Filtration, and Molecular Dynamics Studies

Abstract Histone deacetylases (HDACs) are key regulators of gene expression and have emerged as crucial therapeutic targets for cancer. Among the HDACs, inhibition of the HDAC8 enzyme has been reported to be a novel strategy in the treatment of lung, colon and cervical cancer as well as childhood leukemia. The main objective of this study is to identify, potential, selective and drug‐like HDAC8 inhibitors using a rational drug design approach. In the present study, a combination of pharmacophore based virtual screening (VS) and structure‐based VS were employed to identify HDAC8 inhibitors from Asinex databank containing 666302 molecules. Pharmacophore‐based VS resulted 2000 hits fitness scores of which were ≥ 1.668. Structure‐based VS of resulted hits with HDAC8 returned eight hits having Extra Precision (XP) Glide Score ≤ ‒7.184 kcal/mol. The resultant top eight hits were subjected to molecular docking with other HDACs to identify selective HDAC8 inhibitors. The drug‐like and selective HDAC8 inhibitors thereafter were subjected to Molecular dynamics (MD) simulation. On the basis of fitness score, XP Glide Score, protein‐ligand complex stability, Molecular Mechanics‐Generalized Born Surface Area (MMGBSA) binding energy and drug‐likeness score, compounds 5 and 8 were chosen as the best HDAC8 inhibitors.