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hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A novel environment-sensitive probe S2 with turn-on switch for Human Ether-a-go-go-Related Gene (hERG) potassium channel was developed herein. After careful evaluation, this fluorescent probe showed high binding affinity with hERG potassium channel with an IC50 value of 41.65 nM and can be well applied to hERG channel imaging or cellular distribution study for hERG channel blockers. Compared with other imaging techniques, such as immunofluorescence and fluorescent protein-based approaches, this method is convenient and affordable, especially since a washing procedure is not needed. Meanwhile, this environment-sensitive turn-on design strategy may provide a good example for the probe development for these targets that have no reactive or catalytic activity.

Drug induced long QT syndrome is a high risk event in clinic, which mainly results from their high affinity to the Human Ether-a-go-go-Related Gene (hERG) potassium channel. Therefore, evaluation of the drug's inhibitory activity against the hERG potassium channel is a required step in drug discovery and development. In this study, we developed a series of novel conformation-mediated intramolecular photoinduced electron transfer fluorogenic probes for the hERG potassium channel. After careful evaluation, probes N4 and N6 showed good activity and may have a promising application in the cell-based hERG potassium channel inhibitory activity assay, as well as potential hERG-associated cardiotoxicity evaluation. Compared with other assay methods, such as patch clamp assay, radio-ligand competitive binding assay, fluorescence polarization and potential-sensitive fluorescent probes, this method is convenient and can also selectively measure the inhibitory activity in the native state of the hERG potassium channel. Meanwhile, these probes can also be used for hERG potassium channel imaging without complex washing steps.

The first small-molecule fluorogenic probe A1 for imaging the human Ether-a-go-go-Related Gene (hERG) potassium channel based on the photoinduced electron transfer (PET) off-on mechanism was described herein. After careful biological evaluation, this probe had the potential of detecting and imaging the hERG channel at the molecular and cellular level. Moreover, the competitive binding mechanism of this probe would presumably minimize the effects on the electrophysiological properties of the hERG channel. Therefore, this probe may serve as a powerful toolkit to the hERG-associated study.

Cardiac arrhythmia is a major cause of death in the world. Among many delayed rectifier potassium currents, the rapid delayed rectifier K current (IKr) plays an important role in the repolarization of cardiac tissue. The inhibition of IKr can delay repolarization and lead to an increase in the QT interval of the electrocardiogram, which is the treatment mechanism of Class III antiarrhythmic agents. Therefore, IKr can be considered as the drug target for the treatment of cardiac arrhythmia. In the current study, a series of 4-chromanone compounds (WR1-WR12) were well designed and synthesized as IKr inhibitors. The results disclosed that two compounds displayed potent inhibitory activities against IKr. Moreover, our structure-activity relationship results might provide necessary information for the rational design of inhibitors for IKr.

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.

The hERG potassium channel is a key effector of cardiac repolarization and the blockade of this channel could cause arrhythmia. Thus, hERG channel blockade plays an important role for the potential pro-arrhythmic liability. In this report, binding of blockers to the hERG potassium channel is investigated using a combination of homology modeling, molecular docking, and molecular simulations, where blockade activities are evaluated using the linear regression model of GoldScore fitness. This structure-based virtual screening model is able to estimate the pIC(50) value of a wide range of ligands for the hERG potassium channel. The docked poses for ligands are also consistent with published mutation. Therefore, this model for the prediction of hERG channel blockade has the potential to provide cost-effective virtual screening tools for the evaluation of the cardiac liability of new chemical entities.