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Insights into the Molecular Mechanism of hERG1 Channel Activation and Blockade by Drugs

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Blockade of the human ether-a-go-go related gene 1 (hERG1) channel has been associated with an increased duration of ventricular repolarization, causing prolongation of the time interval between Q and T waves (long QT syndrome, or LQTS). LQTS may result in serious cardiovascular disorders such as tachyarrhythmia and sudden cardiac death. Diverse types of organic compounds bind to the wide intracellular cavity in the pore domain of hERG channels, leading to a full or partial blockade of ion current through the pore. The drug&ndash induced blockade of the hERG-related component of the potassium current is thought to be a major reason for drug&ndash induced arrhythmias in humans. Identification of specific interactions governing the high-affinity blockade of cardiac potassium (K–) channels is crucial both for the prevention of unintended ion channel block and for the design of ion channel modulators. A plethora of ligand- and receptor-based models of K-channels have been created to address these challenges. In this paper, we review the current state of knowledge regarding the structure-function relationship of hERG and discuss progress in the use of molecular modeling for developing both blockers and activators of hERG.
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Keywords: Drugs; anti-arrhythmic activity; antibacterials; antibiotics; antihistamines; astemizole; biological channels; blockers and activators of hERG; channel activation and blockade; cisapride; grepafloxin; hERG; hERG screening; hERG1; ligand- and receptor-based models; long QT syndrome; non-cardiac medications; potent modeling; potent modeling strategies of ion channels; proarrhythmic-drug-induced LQTS; strategies of ion channels; structure-function relationship; terfenadine; transmembrane; ventricular repolarization

Document Type: Research Article

Affiliations: Institute for Biocomplexity and Informatics,Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.

Publication date: 2010-10-01

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