2. Academic Validation
  3. Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline

Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline

  • J Mol Cell Cardiol. 2021 Sep;158:163-177. doi: 10.1016/j.yjmcc.2021.05.015.
Kevin R DeMarco 1,  Pei-Chi Yang 1,  Vikrant Singh 2,  Kazuharu Furutani 3,  John R D Dawson 4,  Mao-Tsuen Jeng 1,  James C Fettinger 5,  Slava Bekker 6,  Van A Ngo 7,  Sergei Y Noskov 7,  Vladimir Yarov-Yarovoy 8,  Jon T Sack 8,  Heike Wulff 2,  Colleen E Clancy 9,  Igor Vorobyov 10
Affiliations

Affiliations

  • 1 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA.
  • 2 Department of Pharmacology, University of California Davis, Davis, CA 95616, USA.
  • 3 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Tokushima 770-8514, Japan.
  • 4 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California Davis, Davis, CA 95616, USA.
  • 5 Department of Chemistry, University of California Davis, Davis, CA 95616, USA.
  • 6 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Department of Science and Engineering, American River College, Sacramento, CA 95841, USA.
  • 7 Centre for Molecular Simulation and Biochemistry Research Cluster, Department of Biological Sciences, University of Calgary, Calgary, AB T2N1N4, Canada.
  • 8 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Department of Anesthesiology and Pain Medicine, University of California Davis, Davis, CA 95616, USA.
  • 9 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California Davis, Davis, CA 95616, USA.
  • 10 Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California Davis, Davis, CA 95616, USA. Electronic address: ivorobyov@ucdavis.edu.
PMID: 34062207 DOI: 10.1016/j.yjmcc.2021.05.015
Abstract

Drug isomers may differ in their proarrhythmia risk. An interesting example is the drug sotalol, an antiarrhythmic drug comprising d- and l- enantiomers that both block the hERG cardiac Potassium Channel and confer differing degrees of proarrhythmic risk. We developed a multi-scale in silico pipeline focusing on hERG channel - drug interactions and used it to probe and predict the mechanisms of pro-arrhythmia risks of the two enantiomers of sotalol. Molecular dynamics (MD) simulations predicted comparable hERG channel binding affinities for d- and l-sotalol, which were validated with electrophysiology experiments. MD derived thermodynamic and kinetic parameters were used to build multi-scale functional computational models of cardiac electrophysiology at the cell and tissue scales. Functional models were used to predict inactivated state binding affinities to recapitulate electrocardiogram (ECG) QT interval prolongation observed in clinical data. Our study demonstrates how modeling and simulation can be applied to predict drug effects from the atom to the rhythm for dl-sotalol and also increased proarrhythmia proclivity of d- vs. l-sotalol when accounting for stereospecific beta-adrenergic receptor blocking.

Keywords

Arrhythmia; Beta-blocker; Enantiomer; Ion channel; Molecular dynamics; Stereochemistry.

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