Thiazole pharmacophore-based discovery of novel SGLT2 inhibitors using virtual screening, molecular docking, and molecular dynamics simulation for diabetic nephropathy

Diabetic nephropathy (DN), a serious complication of chronic diabetes mellitus, remains a leading cause of end-stage renal disease (ESRD). Although therapies targeting the renin-angiotensin-aldosterone system (RAAS) exist, many patients still face progressive renal decline, highlighting the need for improved treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors offer both glycaemic and renal benefits, yet glycosidic inhibitors are associated with adverse effects such as genitourinary infections and euglycemic ketoacidosis. This has prompted interest in non-glycosidic scaffolds. Thiazole, a drug-like heterocycle, shows promise as a core for novel SGLT2 inhibitors. In this study, a ligand-based pharmacophore model (DDHRR_1) was developed using known thiazole-based inhibitors and applied to virtual screening of Drug Central and Enamine libraries. Four compounds olodaterol, nebivolol, Z56768840, and Z8314156464 were identified, with olodaterol showing the most stable interactions during a 100 ns molecular dynamics (MD) simulation. Based on structural insights, a novel compound, NC-1, was rationally designed. NC-1 demonstrated a high pharmacophore fitness score (1.64), favourable docking energy (-11.1 kcal/mol), and stable MD interactions. This integrated computational approach offers a valuable platform for discovering non-glycosidic SGLT2 inhibitors and supports further development of NC-1 for potential treatment of DN.