Molecular Docking Studies Involving the Inhibitory Effect of Gymnemic Acid, Trigonelline and Ferulic Acid, the Phytochemicals with Antidiabetic Properties, on Glycogen Synthase Kinase 3 (α and β)

Type 2 diabetes mellitus (T2DM) accounts for more than 90% of the diabetic population and its prevalence is linked to obesity-induced insulin resistance followed by a relative rate of insulin secretion from the β-cells of the pancreas. Several drugs are available to maintain normoglycemia in diabetic individuals through the regulation of biological functions such as controlling the absorption of glucose in the intestine, increasing the insulin sensitivity, improvement in the secretion of insulin, prevention of excessive breakdown of glucose as well as gluconeogenesis and enhancement of glycogen synthesis. Since, most of the currently available drugs elicit undesirable side effects in addition to the development of resistance after prolonged use, the search for lead molecules preferably from plant origin still continues. Recently, we have formulated a mixture containing three phytochemicals from medicinal plants namely Gymnemic acid, Trigonelline and Ferulic acid in the ratio of 2:3:1 and systematically evaluated its antidiabetic efficacy in type 2 diabetes in rats. Glycogen metabolism plays an important role in the regulation of glucose homeostasis and it is controlled by the two rate-limiting enzymes namely glycogen synthase and glycogen phosphorylase. The activity of glycogen synthase is regulated by glycogen synthase kinase, a negative regulator of insulin signaling pathway. GSK-3 subsists in two similarly associated isoforms namely GSK-3α and GSK-3β with the molecular weight of 51 kDa and 47 kDa, respectively. They possess almost indistinguishable affinities for their substrates and their biological role. The present study is aimed to perform molecular docking studies involving the inhibitory effect of individual phytochemicals with antidiabetic properties on Glycogen synthase kinase-3 (α & β). The binding energy obtained for GA, TG and FA for GSK-3α is found to be −5.33, –6.85, and –7.0 Kcal/Mol, respectively. Likewise, the binding energy calculated for GA, TG, and FA for GSK-3β is found to be –4.69, –5.51, and –5.05 Kcal/Mol, respectively. The data obtained evidenced the inhibitory role of GTF on the activity of GSK isoforms in the regulation of glycogen metabolism.