hERG Channel Physiology and Drug‐Binding Structure–Activity Relationships

Dalibalta, Sarah; Mitcheson, John S.

doi:10.1002/9783527621460.ch4

Cited by 7 publications

(11 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only a few compounds have been identified that do not appear to bind at this position , . In contrast, in a recent study utilizing an automated planar electrode patch clamp system to generate a consistent data set, we were surprised to find that half of 24 LQT compounds that we tested were insensitive to the Y652A mutation . Initial analysis suggests that molecules with an extended conformation and the highest affinity for hERG have a high dependency for Tyr652 while compounds with a more compact conformation are less sensitive to the Tyr mutationperhaps because they are able to reorientate themselves and find alternative energetically favorable binding modes.…”

Section: Structure Of the Drug-binding Sitementioning

confidence: 79%

hERG Potassium Channels and the Structural Basis of Drug-Induced Arrhythmias

Mitcheson

2008

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K + channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias.

show abstract

Section: Structure Of the Drug-binding Sitementioning

confidence: 79%

hERG Potassium Channels and the Structural Basis of Drug-Induced Arrhythmias

Mitcheson

2008

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The human ether‐a‐go‐go–related gene (hERG) potassium channel plays a key role in regulating cardiac excitability and maintaining normal cardiac rhythm. Inhibition of the potassium channels encoded by hERG is considered to be the main mechanism of acquired long QT syndrome 2 . Vonoprazan has been shown to have effects on the hERG channel current at the doses studied with an IC 50 value of 4.8 μg/ml.…”

Section: Figurementioning

confidence: 93%

Vonoprazan‐associated long QT syndrome

Kubo

Sakakibara

Yonezawa

2021

J of Gen and Family Med

View full text Add to dashboard Cite

show abstract

“…Drug induced LQT triggered by hERG inhibition is associated with life-threatening ventricular arrhythmias, so-called Torsades de Pointes (TdP). For an exhaustive review of hERG potassium channel physiology, see Dalibalta and Mitcheson …”

Section: Introductionmentioning

confidence: 99%

QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability

et al. 2012

View full text Add to dashboard Cite

We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability of the best models to predict the activity of 26 proprietary compounds tested in radioligand binding displacement (RBD). Results proved the necessity to use multiple validation sets for a true estimation of model accuracy and demonstrated that using various descriptors and algorithms improves the performance of ligand-based models. Intriguingly, one of the most accurate models uncovered an unexpected link between extent of metabolism and hERG liability. This hypothesis was fairly reinforced by using the Biopharmaceutics Drug Disposition Classification System (BDDCS) that recognized 94% of the hERG inhibitors as extensively metabolized in vivo. Data mining suggested that high Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition, extent of metabolism, active transport, and possibly solubility. Overall, these new findings might improve both the decision making skills of pharmaceutical scientists to mitigate hERG liability during the drug discovery process and the TdP risk assessment during drug development.

show abstract

hERG Channel Physiology and Drug‐Binding Structure–Activity Relationships

Cited by 7 publications

References 85 publications

hERG Potassium Channels and the Structural Basis of Drug-Induced Arrhythmias

hERG Potassium Channels and the Structural Basis of Drug-Induced Arrhythmias

Vonoprazan‐associated long QT syndrome

QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability

Contact Info

Product

Resources

About