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

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 channeldrug 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.

An in silico–in vitro pipeline for drug cardiotoxicity screening identifies ionic pro‐arrhythmia mechanisms

“…In recent years, high‐throughput iPSC‐CM screening approaches that rely on surrogate markers of cardiotoxicity risk have improved prediction accuracy and the ability to evaluate drugs at scale (Bedut et al, 2016; Lu et al, 2019; Pioner et al, 2019). Expression system cell lines and molecular‐dynamic simulations have supplemented these findings by providing detailed single‐channel mechanisms of drug action (Demarco et al, 2020; Yang et al, 2020). However, there have been few methods that provide both measures of cardiotoxicity and mechanism from the same iPSC‐CM cells.…”

A multiscale predictive digital twin for neurocardiac modulation

“…7, where we present an extension of the multiscale model from the atom to the rhythm. Such models were previously used in our studies to predict emergent pro‐arrhythmia proclivities of small‐molecule drugs, blocking cardiac potassium channel encoded by human ether‐à‐go‐go‐related gene (hERG) (DeMarco et al., 2021; Yang et al., 2020). There we used all‐atom molecular dynamics simulations to predict association and dissociation (‘on’ and ‘off ’) rates of hERG blocking drugs to the open channel pore.…”

“…They were computed based on free energy and diffusion coefficient profiles from umbrella sampling molecular dynamics simulations. Those rates were used as parameters of functional kinetic models of state‐dependent hERG channel–drug interactions, which were used to reproduce experimental dose–response curves and incorporated into cardiac cell and tissue models to predict emergent pro‐arrhythmia outcomes (DeMarco et al., 2021; Yang et al., 2020).…”

Case Report of Oral Sotalol on Atrial Fibrillation Conversion and Supraventricular Tachycardia Cardiac Arrhythmia Control

“…The fast delayed-rectifier K+ current, IKr, which is essential for appropriate repolarization of the heart's ventricles, is mediated by potassium channels that are encoded by the human Ether-à-go-go-Related (HERG) gene, according to a recent study. As a result, HERG is a pharmaceutical priority for antiarrhythmic medicines in classes Ia and III [3].…”