Integrated In-Silico Identification and Molecular Dynamics Validation of Potential Inhibitors Targeting Nav1.7 channel

Silent myocardial ischemia (SMI) is defined as the lack of pain during ischemia and is the voltage-gated sodium channel (Nav1.7) has been implicated in the development of nociceptive deficits associated with small fibre neuropathy (SMI). The goal of this study was to use molecular modelling techniques to evaluate Epigallocatechin Gallate (EGCG) as a possible modulator of Nav1.7 via molecular docking analysis, molecular dynamics simulations (300 ns MD) and comparison to other natural products (Curcumin, Resveratrol, Capsaicin, 6-Gingerol) using pharmacokinetic and toxicity predictors. Under our longitudinal assessment, the sustained binding energy of EGCG (-9.5 kcal/mol) was significantly higher than that of any other ligand. The results of MD studies on the physical characteristics of the EGCG-Nav1.7 complex revealed that the sustained 120 ns binding of EGCG to a novel and distinct corner-region binding pocket of Nav1.7 provides a potential allosteric mechanism to modulate Nav1.7 activity. The ADMET analysis showed moderate absorption and low O-availability of EGCG and ProTox-II predictions indicate minimal cardiotoxicity and possible nephrotoxicity associated with EGCG. Together, these data suggest that EGCG is a potential lead compound for targeting Nav1.7-mediated nociceptive dysfunction associated with SMI; warranting further drug development and experimental validation more common with individuals with diabetes.