Multi-Scale Modeling of State-Dependent Drug Binding to the Herg Channel

The hERG channel plays an important role in the repolarization phase of the cardiac action potential. Blockage of the channel conductance can lead to prolongation of the cardiac action potential and the QT interval on the surface electrocardiogram, which may result in deadly arrhythmias. hERG channel blockade is a leading cause for drug withdrawal from the drug development pipeline or marketplace. However, not all hERG-blocking and QT-prolonging drugs cause arrhythmia. Therefore, understanding the molecular mechanisms of drug interactions with the hERG channel and the subsequent modulation of the channel gating leading to different pro-arrhythmia outcomes is crucial for drug design and development.