The human ether-a-go-go related gene (hERG) channels control the inward voltage-gated potassium current IKr that defines ventricular repolarization. Drug-induced inhibition of hERG leads to QT interval prolongation and proarrhythmic events such as Torsade de Pointes.
Non-GLP hERG assay screening is recommended by health authorities and regulatory agencies as an early test in drug discovery to identify compounds with potential hERG liability.
What Is hERG?
hERG (human epithelial potassium voltage-gated channel alpha subunit) is an ion channel that controls the flow of potassium ions in the heart and nervous system. Its inhibition can cause prolongation of the QT interval, which may lead to life-threatening arrhythmias. Therefore, many regulatory bodies recommend or mandate that all drugs be tested for their ability to inhibit hERG.
To meet this requirement, a variety of hERG assays have been developed. These include fluorescence polarization, radioactive ligand binding, and manual or automated patch clamp electrophysiology. Each of these assays has its own advantages and disadvantages. However, manual patch-clamp electrophysiology is considered the gold standard for assessing drug cardiotoxicity by FDA and other regulators.
Because of its complexity and need for specialized equipment, this assay is usually performed only at later stages of the discovery process. For this reason, it is important to develop in silico tools to help identify potential proarrhythmic compounds earlier in the discovery process.
There are a number of in silico models that have been developed to predict hERG potency. These models include pharmacophore and quantitative structure-activity relationship (QSAR) models. Pharmacophore models use a set of molecular features to determine a correlation between a compound and its binding affinity. They have a limited predictive capacity due to the small training datasets they are based on.
How Is It Assayed?
hERG is a cardiac ion channel that plays an important role in the normal ventricular depolarisation/repolarisation (TdP). Virtually all drugs that prolong TdP and result in a QT interval increase block the outward repolarizing current through this channel. As a consequence, hERG blockage has become an accepted surrogate marker for proarrhythmic risk in drug discovery.
The hERG assay is now considered mandatory study under GLP conditions according to ICH S7B and a critical first assessment in early drug development. hERG testing with automated patch-clamp (either IonWorks Barracuda Plus or the PhysioStim cell electrophysiology platform QPatch HTX or SyncroPatch 384PE) is an accurate, reliable and cost-effective screening method to assess a compound’s potential for blocking the hERG channel and causing a long QT interval.
Model Development
In addition to conventional patch-clamp based hERG assays, a number of three-dimensional (3D)-QSAR models have been developed that correlate structural information from a compound’s molecular structure with hERG channel inhibition by regression analysis. Compound properties such as lipophilicity, polarity, flexibility and topological polar surface area have been shown to correlate with hERG blockage in several prediction models.
However, none of the available methods are yet able to predict all compounds with high or low hERG liability. Moreover, the predictive ability of a single property decreases with increasing number of physico-chemical properties used for prediction. Therefore, the integration of several properties is needed to provide a higher confidence of in silico prediction of hERG liability.
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