Computational Discovery of Potential HDAC6 Inhibitors through Integrated Virtual Screening and Molecular Dynamics Approaches

Histone deacetylase 6 has emerged as a significant therapeutic target due to its essential role in neurological, inflammatory, and other pathological conditions. At present, no HDAC6-targeting agents have received FDA approval, and most pipeline candidates exhibit limitations, including insufficient target occupancy, inadequate brain exposure, and poor tolerability. A small number of clinical-stage candidates exist, primarily for non-CNS malignancies. Yet, their pharmacokinetic drawbacks preclude application in neurological diseases associated with HDAC6, underscoring the necessity for new solutions that address these shortcomings. Moreover, these compounds display off-target toxicity attributable to limited selectivity, culminating in adverse reactions among patients. As a result, the emphasis of development over the last ten years has centered on selective inhibitors; nonetheless, no selective and potent HDAC6 inhibitor has yet received approval. The present investigation conducted an integrated virtual screening campaign against HDAC6 using the DrugBank database to identify existing drugs that could be repurposed to suppress HDAC6 activity. The initial assessment consisted of evaluating the binding capacity of molecular entities toward HDAC6. Thereafter, interaction profiling and 500 ns molecular dynamics simulations, combined with essential dynamics, were performed to probe the conformational adaptability and structural stability of HDAC6 upon binding to the identified compounds, specifically penfluridol and pimozide. The virtual screen highlighted penfluridol and pimozide as prospective repurposed therapeutic agents targeting HDAC6, a selection grounded in their binding potency and favorable drug-like characteristics. Docking analyses revealed that penfluridol and pimozide lodge within the same binding cleft on HDAC6 as the reference inhibitor. MD trajectories confirmed the establishment of stable protein–ligand assemblies between HDAC6 and both molecules. Complementary MMPBSA computations yielded favorable binding free energies across all HDAC6–ligand complexes, substantiating the stability of their interactions. Overall, the study indicates that both penfluridol and pimozide bind HDAC6 with strong, favorable interactions, lending credence to the notion of repurposing these agents to treat neurodegenerative disorders. That said, subsequent rigorous investigations remain necessary to delineate their effectiveness and safety profiles within biological settings.