Title:Integrated Ligand and Structure-Based Investigation of Structural Requirements for Silent Information Regulator 1 (SIRT1) Activation
VOLUME: 18 ISSUE: 27
Author(s):Amit K. Gupta and Sun Choi*
Affiliation:National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 03760, National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 03760
Keywords:SIRT1 activators, Imidazothiazole and oxazolopyridine derivatives, 3D QSAR, 2D QSAR, CoMFA, CoMSIA.
Abstract:A series of imidazothiazole and oxazolopyridine derivatives as human Silent Information
Regulator 1 (SIRT1) activators were subjected to the integrated 2D and 3D QSAR approaches. The derived
3D QSAR models yielded high cross-validated q2 values of 0.682 and 0.628 for CoMFA and
CoMSIA, respectively. The non-cross validated values of r2
training
= 0.89; predictive r2
test = 0.69 for
CoMFA and r2=0.87; predictive r2
test =0.67 for CoMSIA reflected the statistical significance of the developed
model. The steric, electrostatic, hydrophobic and hydrogen bond acceptor interactions have
been found important in describing the variation in human SIRT1 activation. Further, 2D QSAR model
for the same dataset yielded high statistical significance and derived 2D model’s parameters corroborated
with the 3D model in terms of features. Derived model was also validated by the crystal structure
of active conformation of SIRT1. Developed models may be useful for the identification of potential
novel human SIRT1 activators as a therapeutic agent.
