Molecular Insights Into Repurposed Drug Interactions With HDAC11 for Advancing Epigenetic Therapeutics in Cancer and Neurodegenerative Diseases

Histone deacetylase 11 (HDAC11) is a member of the HDAC family that plays a crucial role in epigenetic regulation, influencing key cellular processes like transcription, differentiation, and proliferation. Abnormal expressions and functions of HDAC11 have been described in various diseases, including neurodegenerative diseases and cancer, highlighting its potential as a promising therapeutic target. Despite its biological significance, selective HDAC11 inhibitors remain largely unexplored, presenting a critical research gap in the development of targeted epigenetic therapies. Drug repurposing provides a cost‐effective and time‐efficient strategy for accelerating the discovery of novel therapeutics by leveraging the established safety profiles of approved drugs. Here, we report a computational drug repurposing approach to screen FDA‐approved drugs for their ability to inhibit HDAC11. Subsequently, we virtually screened 3500 drugs and shortlisted pimozide and nilotinib as promising candidates, based on high docking scores and protein interaction patterns. Further molecular dynamics (MD) simulations for 500‐ns trajectories demonstrated that pimozide and nilotinib maintain stable protein–ligand contacts with residues lining the HDAC11 catalytic pocket in an AlphaFold‐derived apo model. Because the AlphaFold coordinate file used here does not contain the catalytic Zn 2+ ion, these simulations do not evaluate possible ligand–Zn 2+ coordination or metal‐dependent inhibition. MM‐PBSA‐based binding free energy calculations were conducted to estimate binding propensities in the apo context; however, metal‐aware structural modeling and biochemical assays are required to determine whether observed binding translates to Zn 2+ ‐dependent enzyme inhibition and isoform selectivity.