Computer-based analysis of histone deacetylase 10 and its inhibitor complexes

Abstract

Selective HDAC10 inhibition offers a novel strategy for treating HDAC-related diseases. Using molecular docking, MD simulations, and free energy calculations, key HDAC10 residues (Glu274, Trp205, Asp94) critical for polyamine binding and selectivity were identified. Designed scaffolds such as piperidine-acryl and benzyl-hydroxamates showed stable interactions with HDAC10. N8-acetylspermidine exhibited superior affinity, confirming the importance of ligand conformation. Co-solvent MD simulations supported these findings and helped distinguish HDAC10 from HDAC6 and HDAC8. Furthermore, PROTAC-based degraders targeting HDAC10 were evaluated, and ternary complex simulations demonstrated stable interactions. This study provides a framework for designing selective HDAC10 inhibitors and degraders as potential epigenetic therapies.