<p>The cardiac voltage-gated sodium ion channel (Nav1.5) serves as a crucial regulator of cardiac excitability and presents a potential therapeutic target. While the Sodium-Glucose Cotransporter 2 (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 sodium current (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 inactivation dynamics. The findings provide a foundation for structure-based design of selective modulators targeting sodium channels via allosteric mechanisms.</p>