Key result
hERG1 molecular modeling guides drug development to prevent drug-induced arrhythmias.
Why the study?
Identification of specific interactions governing high-affinity blockade of hERG channels is crucial for preventing unintended ion channel block and designing modulators.
This review summarizes the structure-function relationship of the hERG1 channel and the use of molecular modeling to design its modulators and prevent drug-induced long QT syndrome.
hERG blockade signals ongoing proarrhythmic risk in drug development; review leaves open safer selective modulators.
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– induced blockade of the hERG-related component of the potassium current is thought to be a major reason for drug– 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. Keywords: hERG, biological channels, long QT syndrome, channel activation and blockade, blockers and activators of hERG, hERG screening, potent modeling strategies of ion channels, hERG1, Drugs, ventricular repolarization, ligand- and receptor-based models, structure-function relationship, potent modeling, strategies of ion channels, transmembrane, anti-arrhythmic activity, proarrhythmic-drug-induced LQTS, non-cardiac medications, antibiotics, antihistamines, antibacterials, terfenadine, cisapride, astemizole, grepafloxin
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Durdağı et al. (2010) conducted a review in Long QT syndrome and drug-induced arrhythmias. hERG1 channel blockers and activators was evaluated. Molecular modeling of the hERG1 channel provides insights into its structure-function relationship and aids in the development of both blockers and activators to prevent drug-induced arrhythmias.
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