Key result
In silico modeling of ligand-hERG interactions provides a rational approach for predicting QT-prolongation liability and developing safe non-cardiac agents devoid of hERG blocking activity.
In silico modeling of ligand-hERG interactions offers a rational approach for predicting QT-prolongation liability and developing safer non-cardiac agents.
Incomplete hERG binding data risks TdP in drug development; leaves open structural studies to enable safer cardiac therapies.
The human ether-a-go-go related gene (hERG) potassium channel is critical to the QT interval in the human heart measured by the electrocardiogram (ECG). The blockade of hERG would induce undesired lethal arrhythmia, named torsades de pointes (TdP), a rare but life-threatening symptom. Although a large number of experimental studies on hERG have been conducted so far, knowledge of how known ligands bind to hERG still remains sketchy and has been a major hindrance in the effort to designing novel medicinal molecules devoid of hERG activity in the hope of improving drug safety. This review summarizes several studies on ligand-hERG interactions by in silico receptor-based and ligand-based modeling approaches during recent years. These efforts could aid tremendously in understanding the determinants of ligand binding to hERG channel and the molecular basis of hERG channel blockade, and offer a more rational approach for the prediction of QT-prolongation liability and for the development of novel and safe non-cardiac agents.
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Du et al. (2009) conducted a review in hERG channel blockade and QT-prolongation liability. hERG blockers was evaluated. In silico modeling of ligand-hERG interactions provides a rational approach for predicting QT-prolongation liability and developing safe non-cardiac agents devoid of hERG blocking activity.
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