Integrated ligand and structure-based investigation of structural requirements for silent information regulator activation

A series of imidazothiazole and oxazolopyridine derivatives as human silent information regulator (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 correlation values of r2training = 0.89; predictive r2test = 0.69 for CoMFA and r2=0.87; predictive r2test =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 models parameters corroborated with 3D model in terms of features. The developed model was also validated through the available active conformation structure of SIRT1. Developed models may be useful for the identification of potential novel human SIRT1 activators as therapeutic agent.