Multiscale Computational Analysis of Nav1.5 Modulation by SGLT2 Inhibitors Dapagliflozin and Ertugliflozin: Dual Binding Enhances Allosteric Effects over Single Occupancy

The cardiac sodium channel (Nav1.5) serves as a crucial regulator of cardiac excitability and presents a potential therapeutic target. While the SGLT2 inhibitor dapagliflozin has exhibited cardioprotective effects, its structurally similar counterpart, ertugliflozin, which differs solely by an additional oxygen and methyl group, does not confer cardio-protection. To examine this discrepancy, a multiscale computational approach combining all-atom molecular dynamics (MD) and coarse-grained (CG) simulations was employed to analyze ligand interactions with Nav1.5 in both single and dual-binding site configurations. All-atom simulations revealed localized residue fluctuations but were inadequate for capturing system-wide allosteric effects. Consequently, CG models were derived from atomistic trajectories to improve conformational sampling. Critical residues regulating binding sites were identified through B-factor analyses in three replicas of all-atom models. Harmonic restraints were subsequently applied to these residues within the CG models to simulate ligand-induced rigidity. Notably, in the dual-binding configurations, ertugliflozin’s additional oxygen established a hydrogen bond interaction with Y1767, a mutation site associated with pathological late I _Na . This interaction was absent in single-site configurations and may elucidate the functional divergence between the two compounds. Furthermore, inter-residue distances between the IFMT motif, involving domains III and IV related to channel gating, were monitored to assess inactivation states across the various systems. This investigation underscores how dual-site occupancy and subtle chemical differences in ligands can impact Nav1.5 dynamics. The findings provide a foundation for structure-based design of selective modulators targeting sodium channels via allosteric mechanisms.