Selective inhibition of histone deacetylase 8 (HDAC8) has emerged as a promising approach for treating various diseases, including cancer. However, finding key structural features for HDAC8 inhibition and developing effective and selective HDAC8 inhibitors (HDAC8is) pose significant challenges. In the past few years, the development of various scaffolds for inhibiting HDAC8 has significantly risen and the quest continues. In such cases, N-heterocyclic derivatives (such as thiazine, indole/pyrrole, pyrazole, triazole, indole, etc.) can play a crucial role in the discovery of novel selective HDAC8 inhibitors. In this current work, Bayesian and SARpy QSAR models were established on a structurally diverse set of 188 selective HDAC8 inhibitors after an extensive literature search. QSAR modelling suggests N-heterocyclic rings as important structural fingerprints for selective as well as promising HDAC8 inhibition. Further, molecular docking and molecular dynamics (MD) simulation studies were carried out on selected compounds (4, 15, 36, 40, and 188) containing N-heterocyclic rings to emphasize the significance of these scaffolds in HDAC8 potency. In addition to this, toxicity studies were carried out using density functional theory (DFT) to determine the toxicity profile of investigated compounds which indicated that the compounds are non-toxic. The outcomes of this research will aid in the exploration of certain key directions for the selective HDAC8 inhibitor design that could speed up the search for anticancer drugs.
Keywords: Bayesian classification model; HDAC8 inhibitor; SARpy; molecular docking; molecular dynamics; molecular fingerprints; selectivity.