Residue-level insights into SGLT2 inhibition and Nav1.5 selectivity of gliflozin derivatives: A molecular dynamics...

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins) are widely used to treat type 2 diabetes and cardiovascular diseases. However, emerging evidence suggests that some gliflozin derivatives may also interact with the cardiac sodium channel Nav1.5, underscoring the need to understand the structural basis of target selectivity. In this study, we conducted a residue-level computational analysis of eight clinically relevant gliflozin inhibitors using molecular docking, all-atom molecular dynamics simulations (500 ns, two replicas), and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) binding free energy calculations in a membrane environment. The results show that SGLT2 binding is driven by a conserved hydrogen-bonding network involving key residues, including E99, S287, Q457 and F98, which stabilize the ligand and reduce structural flexibility. In contrast, negative control compounds exhibit weaker binding, greater solvent exposure, and increased residue mobility. Pharmacophore analysis of dapagliflozin reveals that hydroxyl groups within the glucose moiety are essential for binding, and their removal significantly reduces binding affinity. Structural comparison between SGLT2 and Nav1.5 further identifies a steric difference near the chloro-substituent region, where Nav1.5 can accommodate bulkier groups. These findings provide mechanistic insights into ligand binding and offer a structure-based framework for designing gliflozin derivatives with improved Nav1.5 selectivity and reduced SGLT2 activity.