ArticleBiochemical pharmacology2016
Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking.
Article in Biochemical pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 55 citations in OpenAlex.
- Article
- A hERG Blocker Facilitates KbioRxiv : the preprint server for biology · 2026Article
- QbD-Based Formulation Development of Amiodarone Hydrochloride Tablet.Pharmaceutics · 2026Article
- PersonalizedFrontiers in physiology · 2026Article
- Amiodarone irrecoverably impairs the function of human ether-a-go-go-related gene potassium channels.Molecular pharmacology · 2026Article
- Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe.Scientific reports · 2025Article
- Article
- Harnessing AlphaFold to reveal hERG channel conformational state secrets.bioRxiv : the preprint server for biology · 2025Article
- Effect of the Membrane Environment on Pharmacologic Inhibition of hERG KJACC. Clinical electrophysiology · 2025Article
- Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.Current molecular medicine · 2025Article
- Article
- Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide.Cellular and molecular life sciences : CMLS · 2024Article
- Calculations of the binding free energies of the ComprehensiveBiophysics and physicobiology · 2023Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations.Open life sciences · 2023Article
- New Insights into Ion Channels: Predicting hERG-Drug Interactions.International journal of molecular sciences · 2022Article
- Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac KFrontiers in pharmacology · 2022Article
- Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer.EBioMedicine · 2022Article
- Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant.Cellular and molecular life sciences : CMLS · 2021Article
- Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The antiarrhythmic drug amiodarone delays cardiac repolarisation through inhibition of hERG-encoded potassium channels responsible for the rapid delayed rectifier potassium current (IKr). This study aimed to elucidate molecular determinants of amiodarone binding to the hERG channel. Whole-cell patch-clamp recordings were made at 37°C of ionic current (IhERG) carried by wild-type (WT) or mutant hERG channels expressed in HEK293 cells. Alanine mutagenesis and ligand docking were used to investigate the roles of pore cavity amino-acid residues in amiodarone binding. Amiodarone inhibited WT outward IhERG tails with a half-maximal inhibitory concentration (IC50) of ∼45nM, whilst inward IhERG tails in a high K(+) external solution ([K(+)]e) of 94mM were blocked with an IC50 of 117.8nM. Amiodarone's inhibitory action was contingent upon channel gating. Alanine-mutagenesis identified multiple residues directly or indirectly involved in amiodarone binding. The IC50 for the S6 aromatic Y652A mutation was increased to ∼20-fold that of WT IhERG, similar to the pore helical mutant S624A (∼22-fold WT control). The IC50 for F656A mutant IhERG was ∼17-fold its corresponding WT control. Computational docking using a MthK-based hERG model differentiated residues likely to interact directly with drug and those whose Ala mutation may affect drug block allosterically. The requirements for amiodarone block of aromatic residues F656 and Y652 within the hERG pore cavity are smaller than for other high affinity IhERG inhibitors, with relative importance to amiodarone binding of the residues investigated being S624A∼Y652A>F656A>V659A>G648A>T623A.
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