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

Integrated In-Silico Identification and Molecular Dynamics Validation of Potential Inhibitors Targeting Nav1.7 channel | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Integrated In-Silico Identification and Molecular Dynamics Validation of Potential Inhibitors Targeting Nav1.7 channel Harishkaruppiah R, Divya A, A Divya, Tha Thayumanavan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9276510/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Nav1.7 sodium channel Silent myocardial ischemia Epigallocatechin gallate (EGCG) Molecular docking Molecular dynamics simulation Allosteric modulation Diabetic neuropathy Full Text Additional Declarations The authors declare potential competing interests as follows: The author declares that there are no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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. 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