Insilico designing of novel imidazothiadiazole derivatives as SGLT2 inhibitors in emerging potential for Antidiabetic Therapeutics

Abstract

Background. Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induce hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective. Interpretation of molecular docking and physicochemical properties of imidazo (2,1-b)-1,3,4 thiadiazole scaffold as SGLT2 inhibitors. Methods. The chemical structures of 108 molecules were drawn by using Chemdraw professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results. 108 molecules were designed by employing different substitutions on imidazo-thiadiazole nucleus as SGLT2 inhibitors. Out of these 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores as compared to that of canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest dock score of -155.428 and -142.786 respectively. The insilicophysicochemical properties of the best compounds had also been determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion. The imidazo (2,1-b)-1,3,4 thiadiazole scaffold was employed to design a novel SGLT2 inhibitor that exhibits maximum binding interactions with essential amino acids as well orally active.