Exploration of novel inhibitors for class I histone deacetylase isoforms by QSAR modeling and molecular dynamics simulation assays

Histone deacetylases (HDAC) are metal-dependent enzymes and considered as important targets for cell functioning. Particularly, higher expression of class I HDACs is common in the onset ofmultiple malignancies which results in deregulation ofmany target genes involved in cell growth, differentiation and survival. Although substantial attempts have been made to control the irregular functioning of HDACs by employing various inhibitors with high sensitivity towards transformed cells, limited success has been achieved in epigenetic cancer therapy. Here in this study, we used ligand-based pharmacophore and 2-dimensional quantitative structure activity relationship (QSAR) modeling approaches for targeting class I HDAC isoforms. Pharmacophoremodels were generated by taking into account the known IC₅₀ values and experimental energy scores with extensive validations. The QSAR model having an external R2 value of 0.93 was employed for virtual screening of compound libraries. 10 potential lead compounds (C1-C10) were short-listed having strong binding affinities for HDACs, out of which 2 compounds (C8 and C9) were able to interact with all members of class I HDACs. The potential bindingmodes of HDAC2 and HDAC8 to C8 were explored through molecular dynamics simulations. Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms) profiles suggested that proposed hits may be more effective inhibitors for cancer therapy.