Journal of molecular and cellular cardiology, 2021-09, Vol.158, p.163-177
2021
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Details
- Autor(en) / Beteiligte
- Titel
- Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline
- Ist Teil von
- Journal of molecular and cellular cardiology, 2021-09, Vol.158, p.163-177
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •Multi-scale modeling predicted sotalol cardiotoxicity from its stereochemistry.•d- and l- stereoisomers of sotalol have similar hERG channel affinities.•Beta-blocking affinity of l-sotalol is essential for its reduced pro-arrhythmia risks.•Models fit to cell-line hERG inhibition underestimate clinical QT prolongation.•The top-down model optimization was applied to reproduce clinical QT data.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2828eISSN: 1095-8584DOI: 10.1016/j.yjmcc.2021.05.015Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8906354
- Format
- –
- Schlagworte
- Adrenergic beta-Antagonists - chemistry, Adrenergic beta-Antagonists - metabolism, Adrenergic beta-Antagonists - pharmacology, Anti-Arrhythmia Agents - chemistry, Anti-Arrhythmia Agents - metabolism, Anti-Arrhythmia Agents - pharmacology, Arrhythmia, Beta-blocker, Cryoelectron Microscopy - methods, Enantiomer, Ether-A-Go-Go Potassium Channels - antagonists & inhibitors, Ether-A-Go-Go Potassium Channels - chemistry, Ether-A-Go-Go Potassium Channels - metabolism, HEK293 Cells, Humans, Ion channel, Long QT Syndrome - metabolism, Molecular dynamics, Molecular Dynamics Simulation, Myocytes, Cardiac - drug effects, Myocytes, Cardiac - metabolism, Potassium Channel Blockers - chemistry, Potassium Channel Blockers - metabolism, Potassium Channel Blockers - pharmacology, Protein Binding - drug effects, Signal Transduction - drug effects, Sotalol - chemistry, Sotalol - metabolism, Sotalol - pharmacology, Stereochemistry, Stereoisomerism