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 language | English (US) |
|---|---|
| Pages (from-to) | 2945-2954 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 8 |
| DOIs | |
| State | Published - Feb 19 2019 |
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Keywords
- Antiarrhythmic drugs
- Docking
- Local anesthetics
- Molecular dynamics
- Sodium channel
ASJC Scopus subject areas
- General
Cite this
Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel. / Nguyen, Phuong T.; DeMarco, Kevin R.; Vorobyov, Igor; Clancy, Colleen E; Yarov-Yarovoy, Vladimir.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 8, 19.02.2019, p. 2945-2954.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel
AU - Nguyen, Phuong T.
AU - DeMarco, Kevin R.
AU - Vorobyov, Igor
AU - Clancy, Colleen E
AU - Yarov-Yarovoy, Vladimir
PY - 2019/2/19
Y1 - 2019/2/19
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.
KW - Antiarrhythmic drugs
KW - Docking
KW - Local anesthetics
KW - Molecular dynamics
KW - Sodium channel
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U2 - 10.1073/pnas.1817446116
DO - 10.1073/pnas.1817446116
M3 - Article
VL - 116
SP - 2945
EP - 2954
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -