Investigation on the isoform selectivity of histone deacetylase inhibitors using chemical feature based pharmacophore and docking approaches.

A three dimensional (3D) chemical feature based pharmacophore model was developed for selective histone deacetylase 1 (HDAC1) inhibitors, which provides an efficient way to discuss the isoform selectivity of HDAC inhibitors. In contrast to the classical pan-HDAC pharmacophore, two hydrophobic features (HY and HYAr2) were found in the chemical feature based pharmacophore model, which might be responsible for the selectivity of HDAC1 inhibitions. Molecular docking also highlighted the two hydrophobic features, which are located in the internal cavity adjacent to the active site. The results contribute to our understanding of the molecular mechanism underlying the selectivity of HDAC1 inhibitors and suggest a possible target region to design novel selective HDAC1 inhibitors.