A Multi-Method In-Silico Modeling Approach to Discover Novel PotentialSelective HDAC۸ Inhibitors for Therapeutic Cancer Studies

Histone deacetylase ۸ (HDAC۸) is highly expressed in hematological malignancies. Mostavailable HDAC۸ inhibitors possess a hydroxamic acid group, which creates a strong bind withthe zinc ion in HDAC۸. However, this high binding affinity can cause severe side effects.Moreover, other non-selective HDAC۸ inhibitors may have adverse effects. This study aimed toidentify potential, non-hydroxamate, selective, and novel HDAC۸ inhibitors. A pharmacophorehypothesis (AADH-۱) and a quantitative structure-activity relationship (QSAR) model weregenerated using ۶۲ well-known HDAC۸ inhibitors. For virtual screening over۶×۱۰ ۴ moleculesin the ZINC database were applied. For the ۲D-QSAR model, R۲= ۰.۹۰۴۲ for the training setand R۲= ۰.۸۱۸۶ for the test set were calculated and the pharmacophore modeling was validatedwith approved and investigational HDAC۸ inhibitors from DRUGBANK, enhancing itsreliability. The resultant hits with a fitness score > ۱.۷۵ and predicted IC۵۰ < ۸۰ nm werescreened by ADMET predictions (absorption, distribution, metabolism, excretion, and toxicity)and docking investigations. ZINC۰۰۰۰۱۸۹۹, ZINC۰۰۱۸۸۷۷۵, ZINC۰۰۳۷۴۱۰۳, ZINC۰۲۱۰۰۹۲۳, ZINC۰۲۷۶۹۸۹۸, ZINC۰۳۰۳۴۱۷۸, ZINC۰۸۴۲۶۹۹۴, ZINC۳۲۵۵۹۹۲۸ have more affinity towards HDAC۸ and less affinity towards HDAC۳ and HDAC۶. (ZINC۰۰۰۰۱۸۹۹) Penciclovir, used in clinical trials for treating HSV infections, may selectively inhibit HDAC۸ with fewer side effects for related disorders.