%0 Journal Article
%T Molecular Modeling Studies of Thiophenyl C-Aryl Glucoside SGLT2 Inhibitors as Potential Antidiabetic Agents
%A Mukesh C. Sharma
%A Smita Sharma
%J International Journal of Medicinal Chemistry
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/739646
%X A QSAR study on thiophenyl derivatives as SGLT2 inhibitors as potential antidiabetic agents was performed with thirty-three compounds. Comparison of the obtained results indicated the superiority of the genetic algorithm over the simulated annealing and stepwise forward-backward variable method for feature selection. The best 2D QSAR model showed satisfactory statistical parameters for the data set (, , and pred_) with four descriptors describing the nature of substituent groups and the environment of the substitution site. Evaluation of the model implied that electron-rich substitution position improves the inhibitory activity. The good predictive 3D-QSAR models by k-nearest neighbor (kNN) method for molecular field analysis (MFA) have cross-validated coefficient value of 0.7663 and predicted value of 0.7386. The results have showed that thiophenyl groups are necessary for activity and halogen, bulky, and less bulky groups in thiophenyl nucleus enhanced the biological activity. These studies are promising for the development of novel SGLT2 inhibitor, which may have potent antidiabetic activity. 1. Introduction One of the main features of diabetes is the elevation of blood sugar with its deleterious consequences in a variety of tissues [1]. Thus, control of the plasma glucose level is of utmost importance in the treatment of this disease. In recent years, the idea that affecting glucose absorption in the intestine and/or the glucose reabsorption in the kidney might be a possible way to control the sugar level has evolved. Diabetes comprises a group of metabolic disorders characterised by chronic hyperglycaemia with disorders in the metabolism of carbohydrate, fat, and protein that result in defects in secretion and action of insulin [2]. Dysfunction and failure of various organs, especially the eyes, kidneys, nerves, and heart, and the blood vessels are the usual complications of diabetes [3, 4]. Diabetes is mainly divided into four main types including insulin-dependent diabetes mellitus (type 1), non-insulin-dependent diabetes mellitus (type 2), gestational diabetes, and other specific types [5]. Diabetes mellitus type 2 (T2DM) accounts for almost 90% of diabetes cases, with the property of insulin resistance and beta-cell dysfunction that induces hyperglycemia [6]. Medical complications associated with T2DM include cardiovascular disease, stroke, nephropathy, retinopathy, renal failure, and amputations of the extremities [7]. In recent years, much attention has been given to sodium-dependent glucose cotransporters (SGLTs), mediators of reabsorption
%U http://www.hindawi.com/journals/ijmc/2014/739646/