TARGETING INSULIN SIGNALLING PATHWAY AND DPP4 FOR TYPE-II DIABETES

Abstract

Diabetes has become bitter sweet problem of this world. In one of the shocking disclosure, the 20th annual World Diabetes Congress of the International Diabetic Federation has said that India leads the world in the looming epidemic of diabetes. Out of which Types 2 insulin resistance diabetes account for 90 to 95% of all diabetes .The main force driving this increasing incidence is increase in obesity, the single most important contributor to the pathogenesis of diabetes. Although there are many class of drugs available for the treatment of diabetes like insulin, Sulphonylureas, Metformin,, Acarbose but these therapies have limited efficacy, limited tolerability and significant mechanism-based side effects. Thus, newer approaches are desperately needed. Therefore in our study we have selected Gsk3beta, PTP1b and DPP4 as potential targets for drug designing for diabetes. These proteins are involved in insulin signaling pathway and there over expression results in insulin resistance. Although these targets are already reported in literature as negative regulator of insulin signaling but no drug is available in market till date for the same.In this study, we screened a large dataset of Zinc database against Gsk3b, PTP1Band DPP4 using a high throughput approach. The screening was directed toward catalytic site for Gsk3b and DPP4 while in case of PTP1B allosteric site was considered. We also carried out molecular dynamics simulations of the top-scoring compounds in order to study their molecular interactions with the active site functional residues of the targets and also to assess their dynamic behaviour. We report herein prospective non-covalent type inhibitory molecules which are active against Diabetes. These lead molecules possess improved binding properties and are specific of diabetes.