The human ether-à-go-go-related gene (HERG) was isolated in 1994, and shown to encode a six trans-membrane protein that assembles in a tetrameric complex to form the hERG potassium channel. The hERG K+ channel was then demonstrated to conduct the rapid delayed rectifier current (IKr), which is a component of the repolarization phase of the action potential of cardiomyocytes. In recent years, a large amount of evidence has accumulated that drugs belonging to different pharmacological classes may unintentionally block hERG channels, thus causing a prolongation of the action potential duration resulting in the so-called long QT syndrome (LQTS). Drug-induced LQTS predisposes individuals to a potentially lethal form of arrhythmia named torsades de pointes (TdP), and it is therefore not surprising that nowadays in the drug design and development process a great emphasis is cast on methods aimed at an early identification of the hERG blockade potential of new molecules. Several in vitro and in vivo models are currently available for the assessment of the proarrhythmic potential of new chemical entities, but anyway, prediction of drug-induced LQTS is still problematic. On the molecular side, many efforts have been devoted to understanding the determinants of hERG block by drugs, and site-directed mutagenesis combined with the voltage-clamp technique is continuously providing increased and precise information. In silico methods have recently been proposed as a means to increase the capability of predicting hERG liability, and indeed several ligand-based QSAR models have recently appeared in the literature showing good accuracy in assessing the potential for hERG blockade. On the other hand, a parallel development of targetbased studies has been partly hampered by the lack of a sound experimental basis, on which to build a fully reliable model of the channel complex. Nevertheless, in the most recent times, some drug/hERG docking models of increasing quality have started to appear, and despite the limitations imposed by the homology modeling approach, they promise to become useful tools for predicting the hERG binding affinity and interpreting the hERG blockade by small molecules.
Recanatini M (2007). Modeling the hERG potassium channel and its interactions with drugs.
Modeling the hERG potassium channel and its interactions with drugs
RECANATINI, MAURIZIO
2007
Abstract
The human ether-à-go-go-related gene (HERG) was isolated in 1994, and shown to encode a six trans-membrane protein that assembles in a tetrameric complex to form the hERG potassium channel. The hERG K+ channel was then demonstrated to conduct the rapid delayed rectifier current (IKr), which is a component of the repolarization phase of the action potential of cardiomyocytes. In recent years, a large amount of evidence has accumulated that drugs belonging to different pharmacological classes may unintentionally block hERG channels, thus causing a prolongation of the action potential duration resulting in the so-called long QT syndrome (LQTS). Drug-induced LQTS predisposes individuals to a potentially lethal form of arrhythmia named torsades de pointes (TdP), and it is therefore not surprising that nowadays in the drug design and development process a great emphasis is cast on methods aimed at an early identification of the hERG blockade potential of new molecules. Several in vitro and in vivo models are currently available for the assessment of the proarrhythmic potential of new chemical entities, but anyway, prediction of drug-induced LQTS is still problematic. On the molecular side, many efforts have been devoted to understanding the determinants of hERG block by drugs, and site-directed mutagenesis combined with the voltage-clamp technique is continuously providing increased and precise information. In silico methods have recently been proposed as a means to increase the capability of predicting hERG liability, and indeed several ligand-based QSAR models have recently appeared in the literature showing good accuracy in assessing the potential for hERG blockade. On the other hand, a parallel development of targetbased studies has been partly hampered by the lack of a sound experimental basis, on which to build a fully reliable model of the channel complex. Nevertheless, in the most recent times, some drug/hERG docking models of increasing quality have started to appear, and despite the limitations imposed by the homology modeling approach, they promise to become useful tools for predicting the hERG binding affinity and interpreting the hERG blockade by small molecules.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
