Integrated Ligand and Structure-Based Investigation of Structural Requirements for Silent Information Regulator 1...

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.