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

E-ISSN： 1875-628x|15|6|661-670

ISSN： 1570-1808

Source： Letters in Drug Design & Discovery, Vol.15, Iss.6, 2018-04, pp. : 661-670

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Abstract

Background: Sirtuin 2 is a deacylase enzyme which has a significant role in the treatmentof 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 understandthe molecular features and structural requirement of these molecules to selectively inhibit theSIRT-2.

Results: The analysis of pharmacophore model revealed two hydrogen bond acceptors, two hydrogenbond donors and one hydrophobic feature as crucial molecular features that predict bindingaffinity to the SIRT-2 enzyme. The pharmacophore hypothesis (AADDH.7073) derived a 3D-QSARmodel 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-2inhibitors.