Pharmacophore-based virtual screening, 3D QSAR, Docking, ADMET, and MD simulation studies: An in silico perspective...

Histone deacetylase 3 (HDAC3) is an epigenetic regulator that involves gene expression, apoptosis, and cell cycle progression, and the overexpression of HDAC3 is accountable for several cancers, neurodegeneracy, and many other diseases. Therefore, HDAC3 emerged as a promising drug target for the novel drug design. Here, we carried out the pharmacophore modeling using 50 benzamide-based HDAC3 selective inhibitors and utilized it for PHASE ligand screening to retrieve the hits with similar pharmacophore features. The dataset inhibitors of best hypotheses used to build the 3D QSAR model and the generated 3D QSAR model resulted in good PLS statistics with a regression coefficient (R²) of 0.89, predictive coefficient (Q²) of 0.88, and Pearson-R factor of 0.94 indicating its excellent predictive ability. The hits retrieved from pharmacophore-based virtual screening were subjected to docking against HDAC3 for the identification of potential inhibitors. A total of 10 hitsM1 to M10 were ranked using their scoring functions and further subject to lead optimization. The Prime MM/GBSA, AutoDock binding free energies, and ADMET studies were implemented for the selection of lead candidates. The four ligand molecules M1, M2, M3, and M4 were identified as potential leads against HDAC3 after lead optimization. The top two leads M1 and M2 were subjected to MD simulations for their stability evaluation with HDAC3. The newly designed leads M11 and M12 were identified as HDAC3 potential inhibitors from MD simulations studies. Therefore, the outcomes of the present study could provide insights into the discovery of new potential HDAC3 inhibitors with improved selectivity and activity against a variety of cancers and neurodegenerative diseases.