Pharmacophore modelling, validation, 3D virtual screening, docking, design and in silico ADMET simulation study of histone deacetylase class-1 inhibitors

Histone deacetylase class-1 (HDAC class-1) over expression plays an important role during the carcinogenesis by inducing epigenetic silence of tumour suppressor genes. Thus, HDAC class-1 inhibitors have emerged as the promising therapeutic agents for multiple human cancers, since they can obstruct the activity of specific HDACs, restore the expression of some tumour suppressor genes and induce cell differentiation, growth arrest and apoptosis. Validated pharmacophore modelling along with molecular docking study is described here as a rational approach for the development of novel active hits. Pharmacophore model was generated using DISCOtech module and refined by genetic algorithm similarity programme, taking various active inhibitors in the IC50 range of 0.02-72 nM. The best pharmacophore model was validated with receiver operating curve method and Guner-Henry scoring method followed by 3D virtual screening. Several compounds with different structures (scaffolds) were retrieved as hits. After applying the drug likeliness filtering, molecules with the highest Q(fit) values and a known inhibitor were docked in the catalytic domain site of HDAC class-1 for further exploration of the binding mode of these compounds. Finally, in silico pharmacokinetic and toxicities were predicted for active hit molecules which are referred as potential HDAC class-1 inhibitors. Finally, four ligands are designed which fulfil the pharmacophoric requirement and can be further developed as potent hits.