In silico Docking Studies on ATP-Sensitive K+Channel, Insulin Receptor and Phosphorylase kinase Activity by Isolated Active Principles of Stereospermum tetragonum DC

Abstract

INTRODUCTIONATP-sensitive potassium (K ATP ) channels play a central role in glucosestimulated insulin secretion from pancreatic beta cells. Insulin secretion is initiated by closure of the channels and inhibited by their opening. 1The beta-cell K ATP channel is an octameric complex of four pore-forming, inwardly rectifying potassium-channel subunits (Kir6.2) and four regulatory sulfonylurea-receptor subunits (SUR1). Both Kir6.2 and SUR1 are required for correct metabolic regulation of the channel: ATP closes the channel by binding to Kir6.2, and magnesium nucleotides (Mg-ADP and Mg-ATP) stimulate channel activity by interacting with SUR1. Sulfonylureas stimulate insulin secretion in type2 diabetes by binding to SUR1 and closing K ATP channels by an ATP-independent mechanism.2 Insulin receptor belongs to the class of tyrosine kinase receptor. The binding of insulin to its receptor causes conformational changes in the receptor leading to the activation of tyrosine kinase beta subunit. Insulin is responsible for phosphorylation of insulin receptor that leads to glucose uptake by the cells. Insulin is secreted by pancreatic islets in response to increase in blood glucose levels. Most cells of the body have insulin receptors which bind the insulin that is present in the blood circulation. When insulin is attached to insulin receptor of the cell, it initiates a cascade of events that mediates the absorption of glucose from the blood into the cell.3 Phosphorylase kinase (PhK) is the regulatory enzyme responsible for catalyzing the rate limiting step in glycogen breakdown. PhK activates glycogen phosphorylase resulting in degradation of glycogen to glucose-1-phosphate. In liver, these reactions allow for the maintenance of blood glucose, and in muscle, they lead to energy production to sustain muscle contraction. It is comprised of four different subunits with a stoichiometry of (α,β, γ, δ).α,β, and δ are regulatory, while γ is catalytic. The α subunit is encoded by two different genes. 4,5 The objective of the present study was to investigate the in silico antidiabetic effects of the isolated compound 1,4a,5,7a-tetrahydro-5-hydroxy-7-(hydroxymethyl) -1 -(tetrahydro-6-(hydroxymethyl) -3,4,5-trimethoxy-2H-pyran-2-yloxy) cyclopenta (c) pyran -4 -carboxylic acid and 5,8-dihydro-7-isopentyl-2,3,5,8-tetramethoxynaphthalene-1,4,6-triol. MATERIALS AND METHODS Collection of plant materialsThe root parts of S. tetragonum (family: Bignoniaceae) was collected from Tirunelveli district of Tamil Nadu, India and identified by the taxonomist of TBGRI and a voucher specimen (TBGRI 8282) has been deposited in the institute herbarium. Aqueous extraction of dry powderTo prepare water extract, the powder S. tetragonum was extracted with distilled water (5 g/100 ml) by stirring for 4 hours and then filtering

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