Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel

Phuong T. Nguyen, Kevin R. DeMarco, Igor Vorobyov, Colleen E Clancy, Vladimir Yarov-Yarovoy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The human voltage-gated sodium channel, hNa V 1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNa V 1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNa V 1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNa V 1.5 and will be useful for rational design of novel therapeutics.

Original languageEnglish (US)
Pages (from-to)2945-2954
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number8
DOIs
StatePublished - Feb 19 2019

Fingerprint

Sodium Channels
Anti-Arrhythmia Agents
Drug Interactions
Molecular Dynamics Simulation
Local Anesthetics
Anesthetics
Pharmaceutical Preparations
Voltage-Gated Sodium Channels
Drug Design
Drug Delivery Systems
Molecular Structure
Action Potentials
Binding Sites
Therapeutics

Keywords

  • Antiarrhythmic drugs
  • Docking
  • Local anesthetics
  • Molecular dynamics
  • Sodium channel

ASJC Scopus subject areas

  • General

Cite this

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abstract = "The human voltage-gated sodium channel, hNa V 1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNa V 1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNa V 1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNa V 1.5 and will be useful for rational design of novel therapeutics.",
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AU - Nguyen, Phuong T.

AU - DeMarco, Kevin R.

AU - Vorobyov, Igor

AU - Clancy, Colleen E

AU - Yarov-Yarovoy, Vladimir

PY - 2019/2/19

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N2 - The human voltage-gated sodium channel, hNa V 1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNa V 1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNa V 1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNa V 1.5 and will be useful for rational design of novel therapeutics.

AB - The human voltage-gated sodium channel, hNa V 1.5, is responsible for the rapid upstroke of the cardiac action potential and is target for antiarrhythmic therapy. Despite the clinical relevance of hNa V 1.5-targeting drugs, structure-based molecular mechanisms of promising or problematic drugs have not been investigated at atomic scale to inform drug design. Here, we used Rosetta structural modeling and docking as well as molecular dynamics simulations to study the interactions of antiarrhythmic and local anesthetic drugs with hNa V 1.5. These calculations revealed several key drug binding sites formed within the pore lumen that can simultaneously accommodate up to two drug molecules. Molecular dynamics simulations identified a hydrophilic access pathway through the intracellular gate and a hydrophobic access pathway through a fenestration between DIII and DIV. Our results advance the understanding of molecular mechanisms of antiarrhythmic and local anesthetic drug interactions with hNa V 1.5 and will be useful for rational design of novel therapeutics.

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