ArticleJournal of molecular and cellular cardiology2021
Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline.
Article in Journal of molecular and cellular cardiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 23 citations in OpenAlex.
- Neuronal safety of Kv11.1 blockers: Patch-clamp and in vitro evaluation with physiologically based pharmacokinetic (PBPK) modeling.Toxicology reports · 2026Article
- Prediction of TdP Arrhythmia Risk Through Molecular Simulations of Conformation-specific Drug Interactions with the hERG KbioRxiv : the preprint server for biology · 2025Article
- The Therapeutic Potential of Propranolol and Other Beta-Blockers in Hyperthyroidism.International journal of molecular sciences · 2025Review
- Article
- Harnessing AlphaFold to reveal hERG channel conformational state secrets.bioRxiv : the preprint server for biology · 2025Article
- A multiscale predictive digital twin for neurocardiac modulation.The Journal of physiology · 2023Article
- On the importance of ryanodine receptor subunit cooperativity in the heart.Biophysical journal · 2023Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- An in silico-in vitro pipeline for drug cardiotoxicity screening identifies ionic pro-arrhythmia mechanisms.British journal of pharmacology · 2022Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
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.
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Registered trials
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