Ligand and structure based pharmacophore modeling to facilitate novel histone deacetylase 8 inhibitor design.

Over expression of histone deacetylases (HDACs) leads to the suppression of various gene expressions including cancer suppressor gene. Thus, novel inhibitors of these enzymes can be a valid method to treat cancers. To facilitate the discovery of novel HDAC8 inhibitors, pharmacophore models were generated using ligand and receptor based approaches and validated with a database of active and inactive compounds. These validated pharmacophores have effectively been used in search of three databases and final hits were subjected to molecular docking using GOLD 4.1 program. Hit compounds that scored high GOLD fitness scores and showed interactions with catalytically important residues and metal ions were considered. Finally, three compounds have been reported as novel virtual leads to design potent HDAC8 inhibitors.