Identification of Novel SGLT‐2 Inhibitors Against Diabetes Mellitus Type 2: A Multiphase Computational Approach

Abstract In the proximal tubule, glucose is reabsorbed from glomerular filtrate via membrane protein known as sodium‐glucose cotransporter 2 (SGLT‐2). The study aim was to identify novel therapeutic approaches to treat diabetes mellitus type 2 by inhibiting main protein SGLT‐2. The pharmacokinetics prediction exhibited good parameters of top three compounds, suggesting them for further computational screening. Next, the top three compounds‐SGLT‐2 complexes were subjected to a 100 ns simulation run. Upon analyzing the simulation trajectories, MSID000065 was found to be more stable, compact, and less deviated, followed by MSID000058, ZINC000005425464, and control. The MSID000065 was noted with more unique interactions Asp–Arg and Glu–Lys, indicating its stability and rigidity. To further validate the docking studies, binding free energy was calculated by the molecular mechanics Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics generalized born surface area (MMGBSA) approaches and the MSID000065 was noted with −61.14 kcal/mol binding, suggesting its stability. The compounds MSID000058, ZINC000005425464, and control were noted with binding energy scores of −57.95, −52.36, and −50.57 kcal/mol. The findings suggested that the current computational work can help provide a foundation for the identification of SGLT‐2 inhibitors. Experimental research must be conducted to determine the efficiency of the lead compounds.