Mon, 18 Dec 2017

Identification of Novel HDAC8 Inhibitors Using Pharmacophore Based Virtual Screening, 3D QSAR and Molecular Docking Approach

Sudhan Debnath1*, Payel Nath1, Ranendu Kumar Nath2

1. Department of Chemistry, MBB College, Agartala, Tripura, 799 004, India

2. Department of Chemistry, Tripura University, Suryamanninagar, Agartala, Tripura, India


ABSTRACT

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.

Keywords: Pharmacophore, Virtual screening, atom based 3D QSAR, HDAC8 inhibitors, Docking.


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