Pharmacophore modeling and virtual screening studies to design some potential histone deacetylase inhibitors as new leads.

Histone deacetylase is one of the important targets in the treatment of solid tumors and hematological cancers. A total of 20 well-defined inhibitors were used to generate Pharmacophore models using and HypoGen module of Catalyst. These 20 molecules broadly represent 3 different chemotypes. The best HypoGen model consists of four-pharmacophore features--one hydrogen bond acceptor, one hydrophobic aliphatic and two ring aromatic centers. This model was validated against 378 known HDAC inhibitors with a correlation of 0.897 as well as enrichment factor of 2.68 against a maximum value of 3. This model was further used to retrieve molecules from NCI database with 238,819 molecules. A total of 4638 molecules from a pool of 238,819 molecules were identified as hits while 297 molecules were indicated as highly active. Also, a Similarity analysis has been carried out for set of 4638 hits with respect to most active molecule of each chemotypes which validated not only the Virtual Screening potential of the model but also identified the possible new Chemotypes. This type of Similarity analysis would prove to be efficient not only for lead generation but also for lead optimization.