Sudhan Debnath

In the present study a series of 20 histone deacetylase 8 (HDAC8) inhibitors were used for generation of pharmacophore. A five features pharmacophore with one hydrogen bond acceptor (A), two hydrogen bond donors (DD) and two ring aromatics (RR) was developed and used for searching compound database. A statistically significant atom based 3D QSAR model was built by selecting best pharmacophore hypothesis ADDRR.3 with R2 = 0.9821 for training set of 14 molecules and Q2= 0.7314, RMSE= 0.1709, Person-R= 0.9061 for test set of 6 molecules. These parameters indicate that the model is a good predictive model. Docking study of known inhibitors as well as hits resulted after data base searching having fitness score ≥ 1 was performed. Docking analysis shows the important residues in the active site of receptor are Zn-388, TYR-306, HIS-142, PHE-152, PHE-208, GLY-151, and HIE-180. The XP glide score of highest active compound 1 and lowest active 20 are -11.73 and -6.036 respectively, which corroborated with experimental activity. On the basis of pharmacophore matching, predicted activity and docking interactions 5 novel chemical scaffold (Code No: CACPD2011a-0001275680, CACPD2011a-0000573705, CACPD2011a-0001843791, CACPD2011a-0000300107, CACPD2011a-0000291783) are reported as potent HDAC8 inhibitors.

In the present study structure based virtual screening of compound data base, prediction of activity of high extra precision glide docking scored (XPGS) molecules by atom based 3D QSAR model, XP glide docking analysis of known inhibitors to know the key residue interactions and ADME study of identified Histone Deacetylase 2 (HDAC2) inhibitors were performed. A 3D QSAR model was build for both training set (R2 = 0.9867, SD= 0.104, F= 322.1 and N= 17) and test set (Q2 = 0.9137, Pearson r= 0.9671, RMSE = 0.160, N = 7) molecules and showed a statistically significant and good predictive model. The visualization of 3D QSAR model suggested that introduction of hydrogen bond donor group in 5-position of pyridine ring, 6-position of 1,2-diaminobenzene ring; hydrophobic groups in the 2,4-position of pyridine ring, 5,6 -position of 1,2-diamino benzene ring, 2,3,5,6-position of amonomethylbenzamide ring of highest active compound 1 were suitable to increase the HDAC2 inhibitory activity. The XP glide docking analysis of the known inhibitors showed that residues PHE-155, Gly-154, His-145, His-146, Asp-104 and Zn-ligand interaction in the active site region play a crucial role for inhibitory activity. The activity of high glide scored molecules resulted from virtual screening were predicted by atom based 3D QSAR model. After prediction of activity the molecules were subjected to ADME study to know the drug likeness properties and reported 10 molecules having XPGS > 12.0 and predicted activity > 6.7 as potent HDAC2 inhibitors. The docking interaction of known inhibitors was also similar to the docking interaction of identified ten potent inhibitors.