Docking-enabled pharmacophore model for histone deacetylase 8 inhibitors and its application in anti-cancer drug discovery.

Zinc-dependent histone deacetylase 8 removes the epsilon-acetyl groups present in the N-terminal lysine residues of histone proteins, thereby restricting various transcription factors from being expressed. Inhibition of this enzyme has been reported to be a novel strategy in cancer treatment. To identify novel and diverse leads for use in potent histone deacetylase 8 inhibitor design, a pharmacophore model showing high correlation between experimental and estimated activities was generated using the best conformations of training set compounds from molecular docking experiments. The best pharmacophore model was validated using four different strategies and then used in database screening for novel virtual leads. Hit compounds were selected and subjected to molecular docking using GOLD. The top-scored compound was further optimized for improved binding. The optimization step led to a new set of compounds with both improved binding at the active site and estimated activities. The identified virtual leads could be used for designing potent histone deacetylase 8 inhibitors as anti-cancer therapeutics.