A Theoretical Investigation of the Structural Mechanism Underlying the Effect of EGCG on the Cardiac Sodium Channel

Introduction: The cardiovascular benefits of epigallocatechin-3-gallate (EGCG) have been linked to its action on multiple targets, including Nav1.5 channels. EGCG inhibits these channels in a dose-dependent manner and alters their voltage-dependence of inactivation. However, the molecular mechanism of this effect remains unresolved. Therefore, the main objective of this study is to investigate potential mechanisms contributing to EGCG-induced Nav1.5 inhibition. Methods: Mathematical simulations incorporating the experimentally observed Nav1.5 gating alterations induced by EGCG were conducted. Molecular docking and molecular dynamics (MD) simulations were then used to investigate possible EGCG-Nav1.5 structural interactions. Results: Electrophysiological simulations, based solely on EGCG-induced gating alterations, reproduced approximately 39% of the experimentally observed reduction in INa, indicating that additional mechanisms contribute to the full effect of EGCG on Nav1.5. Structural modeling suggested that EGCG may interact within the central cavity of Nav1.5, involving residues in proximity to the DIII and DIV domains and fenestration regions. These findings are consistent with a potential interaction within the pore region, although they do not demonstrate a direct functional blocking mechanism. Discussion: The combined results suggest that the EGCG effect on Nav1.5 cannot be explained exclusively by gating modulation and likely involves additional non-gating contributions. Structural data support the possibility of an interaction within the channel pore, but no direct evidence of pore blockade or fenestration-mediated access was obtained. Conclusion: EGCG-induced Nav1.5 inhibition likely involves both modulation of channel gating and additional interactions whose structural basis remains to be defined.