Pharmacophore and 3D-QSAR Characterization of Thieno[3,2-d] pyrimidine-6-carboxamides as SIRT-2 Inhibitors

Abstract

Background: Sirtuin 2 is a deacylase enzyme which has a significant role in the treatment of neurodegenerative diseases. A reported series of novel thieno[3,2-d]pyrimidine-6- carboxamide derivatives has been chosen as sirtuin inhibitors. Methods: A pharmacophore and atom-based 3D-QSAR studies were carried out in order to understand the molecular features and structural requirement of these molecules to selectively inhibit the SIRT-2. Results: The analysis of pharmacophore model revealed two hydrogen bond acceptors, two hydrogen bond donors and one hydrophobic feature as crucial molecular features that predict binding affinity to the SIRT-2 enzyme. The pharmacophore hypothesis (AADDH.7073) derived a 3D-QSAR model with significant Partial Least Square (PLS) statistics values as r2= 0.9604, SD= 0.2568, F= 137.5, for training set and Q2= 0.9515, RMSE= 0.2045, Pearson-R= 0.9758, for the test set. Conclusion: The results provide a detailed structural insights of thieno[3,2-d]pyrimidine-6- carboxamide derivatives which can provide guidance to develop novel potent and selective SIRT-2 inhibitors. Keywords: SIRT2 inhibitor, pharmcophore, 3D-QSAR, molecular modeling, PLS, deacylase enzyme.