Integrated ligand and structure-based investigation of structural requirements for silent information regulator [SIRT1] activation

Abstract

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 q 2 values of 0.682 and 0.628 for CoMFA and CoMSIA respectively. The non-cross validated correlation values of r 2 training = 0.89; predictive r 2 test = 0.69 for CoMFA and r 2 =0.87; predictive r 2 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 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. Keywords: SIRT1 activators, imidazothiazole and oxazolopyridine derivatives, 3D QSAR, 2D QSAR, CoMFA and CoMSIA. heterocyclic analogs [19], 1,4-dihydropyridine analogs [20], resveratrol analogues [21, 22], and some quinoxaline analogs [23]. The crystal structure of human SIRT-1 protein with its small molecule activator was unknown until recently [24], thus few ligand-based studies have been reported on SIRT1 activators [25,26]. However, no quantitative validation of the reported models has been reported in these studies. Our past successful efforts of integrated ligand-and structure-based drug discovery on other targets [27,28,29,30] encouraged us to use this approach in the presented project. We herein report a ligand-based 3D QSAR models using known SIRT1 activators and its validation through available crystal structure of SIRT1. Methodology DatasetThe QSAR studies have been performed on a dataset of fifty compounds belonging to Imidazothiazole and Oxazolopyridine class having human SIRT1 activation potency with EC1.5 values ranging from 0.16µM to 130µM [18,19]. Activation in the assay was measured as the concentration of compound required to increase the enzyme activity by 50% (EC1.5). The EC1.5 values were converted into negative logarithm of EC1.5 (pEC1.5) for the use in the QSAR studies.The fifty compounds in the dataset were rationally distributed into a training set of 26 molecules and a test set of 24 molecules to generate the QSAR models and evaluate the predictive ability of the developed models respectively. The chemical structures along with their biological activity of all the dataset compounds have been shown in Figure1, Table1 and Table 2.Please insert Figure 1 about here. Table 1 about here. Please insert