Postprandial hyperglycemia, a hallmark of type 2 diabetes mellitus, is often mitigated through the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors, which function to lower blood glucose levels by promoting glucose excretion in the urine. Empagliflozin and sotagliflozin are examples of such inhibitors. The molecular mechanism and efficiency of these drugs on SGLT2 variants are less understood. In this study, the effectiveness of empagliflozin and sotagliflozin on the SGLT2 protein variants, including native, V95I, V157A, L283M, and F453A, has been investigated to explore the extent and mechanism of action of these drugs on the protein's function. The molecular docking technique was used to investigate the interactions between empagliflozin, sotagliflozin, and the SGLT2 protein. The three-dimensional structures of the protein and ligands were retrieved from the Protein Data Bank (PDB) and PubChem databases, respectively. Ligand structures were optimized using the Avogadro software. Molecular docking simulations were subsequently performed using AutoDock Tools and the Vina algorithm. Binding affinities and interacting amino acid residues were then analyzed. An inverse correlation was observed between binding energy and structural variation, indicating that the introduced variants negatively impacted drug performance, diminishing the efficacy of empagliflozin and sotagliflozin. Specifically, the F453A variant, characterized by a mutation in Phe453- a critical residue for ligand binding- presented the largest structural variation and lowest binding energies to the drugs (-10.1 kcal/mol for empagliflozin and -9.4 kcal/mol for sotagliflozin). This reduction in binding affinity would impede the drugs' capacity to lower blood glucose levels, thus underscoring the significance of Phe453.
Sadeghi et al. (Mon,) studied this question.