Abstract

MOLECULAR DESIGNING AND DOCKING STUDIES ON SOME NOVEL 5-ARYL 1,3,4-THIADIAZOLE DERIVATIVES AS INSULYSIN INHIBITORS

Sherin Abdul Hameed*, Joyamma Varkey and Jayasekhar Parameswaran Nair

ABSTRACT

Diabetes mellitus (DM) is a leading non-communicable disease which affects more than100 million people worldwide and is considered as one of leading diseases which causes death in the world. Type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Insulin degrading enzyme (IDE, Insulysin), a structurally distinctive zinc metallopeptidase, is a best characterized mediator of insulin catabolism. IDE deficit increases the abundance and signalling of pancreatic hormones insulin, amylin and glucagon. Therefore, agents that inhibit the activity of IDE would be a viable approach towards treatment of T2DM. In the present study, a series of 5-aryl-1,3,4 -thiadiazole derivatives were designed and subjected to in silico screening for drug likeness and desired molecular properties compared with probe ML345. Those analogues having best molecular parameters and good PASS score are selected for molecular docking studies using the docking software Discovery studio 2018. Only 12 of them showed significant interaction with the target protein. PA33 and PA34 have good docking score and more hydrogen bonding interactions with active site residues of Insulysin protein target (PDB ID: 2G47 and 3E4A). From the docking studies, the best pose for the compounds were obtained with least energy value. With all these results, it can be hypothesized that these compounds can be considered as potential inhibitors of Insulysin (IDE) that could hold therapeutic value for the treatment of diabetes.

Keywords: Insulysin, insulin degrading enzyme, 1,3,4-thiadiazole, diabetes mellitus, molecular docking.