Spatial and electronic features driving SGLT1/2 selectivity: a combined molecular dynamics and quantum mechanics study.

The rising global prevalence of diabetes underscores the need for highly selective sodium-glucose cotransporter (SGLT) inhibitors, which are essential for glucose regulation. While human Na-D-glucose cotransporter (hSGLT) inhibitors offer therapeutic potential, the high sequence similarity between SGLT1 and SGLT2 complicates selective inhibitor design. To elucidate the selective inhibition mechanisms of SGLT1/2, molecular dynamics (MD) simulations and quantum calculations were combined to explore SGLT1/2 inhibition mechanisms. Microsecond-level MD simulations were performed on 22 SGLT protein-ligand complexes and 97 highly selective inhibitors were used in the DFT calculations. Our results highlight that spatial complementarity between ligands and SGLT binding pockets is key to selectivity. For example, SGLT1-selective ligands with trifluoromethyl or isopropyl groups on the pyrazole ring optimize interactions with ASN78. In SGLT2, GLN457 forms two stable hydrogen bonds with high-selectivity inhibitors but only one with low-selectivity ligands, explaining selectivity differences. Comprehensive DFT calculations of critical non-covalent interactions elucidated their stability and strength. Additionally, atomic dipole moment corrected Hirshfeld charge calculations revealed ligand charge distribution differences, clarifying their behaviors in MD simulations and providing insights into molecular design. In conclusion, this study elucidates the selective mechanisms of SGLT1 and SGLT2, with a comprehensive examination of the differences in their binding pockets, offering valuable insights for designing highly selective inhibitors.