Mon, 18 Dec 2017

In Silico Discovery of Small Molecule HDAC2 Inhibitors using Virtual Screening, Atom based 3D QSAR Model, Docking Analysis and ADME study

Sudhan Debnath*1,Rajarshi Banik1, Tanusree Debnath1

1. Department of Chemistry, MBB College, Agartala, Tripura, India 799004.


ABSTRACT

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.

Keywords: HDAC2 inhibitors, Virtual Screening, 3D QSAR, Docking, ADME study


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