Structure-based Drug Designing Recommends HDAC6 Inhibitors to Attenuate Microtubule-associated Tau-pathogenesis.

Protein acetylation and deacetylation play vital roles in the structural and physiological behavior of target proteins. Histone deacetylase 6 (HDAC6) remains a key therapeutic target in several chronic diseases such as cancer, neurodegenerative, and hematological diseases. In tau-pathogenesis, HDAC6 tightly regulates microtubule-associated tau physiology, and its inhibition suppresses Alzheimer's phenotype. To this end, the current study has identified novel HDAC6 inhibitors by structure-based drug designing method. A pharmacophore was generated from HDAC6 in complex with trichostatin A. The selected pharmacophore had five features including two hydrogen bond donors, one hydrogen bond acceptor, and two hydrophobic. Pharmacophore validation obtained highest GH score of 0.80. By applying Lipinski's rule of five and ADMET Descriptors, a drug-like database of 29,183 molecules was generated from the Zinc Natural Product Database. The validated pharmacophore screened 841 drug-like molecules, and subsequently subjected to molecular docking in the active site of HDAC6. Molecular docking identified 11 hits, where they showed highest ChemPLP score (> 90.00), stable conformation, and hydrogen bond interactions with catalytic residues of HDAC6. Finally, molecular dynamics simulation identified three molecules as potent HDAC6 inhibitors with stable root mean square deviation and highest number of hydrogen bonds with the catalytic residues of HDAC6. Overall, we recommend three novel inhibitors of HDAC6, capable of suppressing the microtubule-associated tau-pathogenesis.