A Computational Study of New Glitazones‐Sulphonylureas Hybrids as Potential Antidiabetic Agents

Abstract

Abstract Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder with global cases expected to increase significantly in the coming decades. Existing treatments include sulphonylureas and thiazolidinediones (TZDs), which target insulin secretion and sensitivity. Hence, in this study, we have virtually designed a new hybrid of 2,4‐thiazolidinedione‐sulphonylureas 6a‐r by utilizing molecular hybridization of sulphonylurea and TZD moieties to enhance and improve their antidiabetic efficacy and bioavailability while eliminating their side effects. Furthermore, we have used computational techniques to evaluate the antidiabetic and pharmacokinetic properties of hybrids 6a‐r . The docking study of hybrids 6a‐r was assessed against five key proteins: α‐glucosidase, α‐amylase, PPAR‐γ, DPPIV, and SGLT2. The SwissADME and PkCSM results revealed the favorable pharmacokinetic profiles and acceptable toxicity. Amongst the 2,4‐thiazolidinedione‐sulphonylurea hybrids 6a‐r investigated, glitazone 6c and rhodanine 6k emerged as the best inhibitors of DPPIV and SGLT2 with binding free energies of −38.76 kcal/mol and −36.45 kcal/mol respectively, as well as corresponding docking scores of −8.78 and −6.28 kcal/mol. Furthermore, molecular dynamics simulations confirmed the stability of these binding to the enzymes' active sites. These findings suggest that glitazone and rhodanine hybrids can act as DPPIV and SGLT2 inhibitors, thus assisting in the drug discovery of new potential antidiabetic agents.