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

Kevin R. DeMarco, Pei Chi Yang, Vikrant Singh, Kazuharu Furutani, John R.D. Dawson, Mao Tsuen Jeng, James C. Fettinger, Slava Bekker, Van A. Ngo, Sergei Y. Noskov, Vladimir Yarov-Yarovoy, Jon T. Sack, Heike Wulff, Colleen E. Clancy, Igor Vorobyov

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)163-177
Number of pages15
JournalJournal of Molecular and Cellular Cardiology
Volume158
DOIs
StatePublished - Sep 2021

Keywords

  • Arrhythmia
  • Beta-blocker
  • Enantiomer
  • Ion channel
  • Molecular dynamics
  • Stereochemistry

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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