Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

Abstract

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study Tanusree Debnath,1 Swapan Majumdar,2 Arunasree M Kalle,3 Vema Aparna,4 Sudhan Debnath1 1Department of Chemistry, MBB College, Agartala, Tripura, 2Department of Chemistry, Tripura University, Suryamanninagar, Agartala, Tripura, 3University of Hyderabad Gachibowli, Hyderabad, 4Sree Chaitanya Institute of Pharmaceutical Sciences, Karimnagar, India Abstract: In recent years, histone deacetylases (HDACs) have been considered one of the promising targets for cancer chemotherapy. In the present study, a six-featured pharmacophore model with two hydrogen bond acceptors (AA), two hydrogen bond donors (DD), and two aromatic rings (RR) was developed. A predictive three-dimensional quantitative structure–activity relationship model was generated using the pharmacophore models obtained. The model has an excellent correlation coefficient and good predictive ability, as shown by the significant statistical parameters for both the training set (R2=0.9565, standard deviation =0.1171, F=99, and number of ligands in training set =21) and test set (Q2=0.8468, Pearson's R=0.9363, number of ligands in test set =9) molecules. The pharmacophore model was employed for the virtual screening of molecules with HDAC8 activity. The screening resulted in 366 hits with predicted activity as HDAC8 inhibitors. The hits obtained from the virtual screening were subjected to a molecular docking study to identify the potent inhibitors that binds to the active site with high affinity. The molecular docking study of known inhibitors and their analysis showed that the crucial interacting amino acid residues of HDAC8 are TYR-306, HIS-142, PHE-152, TYR-100, HIE-180, PHE-207, and Zn-388. On the basis of fitness score, predicted activities, XP Glide score, ADME results, and interacting amino acid residues, ten structurally diverse hits were reported in this paper as HDAC8 inhibitors. Keywords: pharmacophore, atom-based 3D QSAR, virtual screening, docking, ADME, HDAC8 inhibitors