Ligand based pharmacophore modelling of anticancer histone deacetylase inhibitors

Abstract

Histone deacetylases have emerged as an important therapeutic target for the treatment of cancer. Genome-wide histone hypoacetylation causes many cancers. Recently, inhibitors of histone deacetylases (HDAC) have emerged as an important class of anticancer agents. Various side effects
like myocardium damage and bone marrow depression even leading to cell death have been observed in the treatment of caner cells using HDAC inhibitors. The discovery and development of type-specific HDAC inhibitors is of both research and clinical interests. Ligand based pharmacophore modelling is playing a key role for the identification of ligand features for the particular targets. We present a model for designing the pharmacophore onto the set of 70 compounds of three different classes and two subclasses. The ligand based pharmacophore model has been identified in order to facilitate the discovery of type specific anticancer HDAC inhibitors. The result indicates that the in silico methods
are useful in predicting the biological activity of the compound or compound library by screening it against a predicted pharmacophore. Ligand Scout 2.02 has been used to predict the pharmacophore
features for anticancer HDAC inhibitors and the distances between pharmacophore features have been calculated through the software Jmol. The proposed model has been validated by docking the MS275
compound into the binding pocket of Human HDAC8. Our discovery will help in the identification of more specific anticancer human HDAC inhibitors.