Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Abstract

The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug-hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC(50)) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC(50) values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC(50) data available in accessible scientific literature to provide a high-quality data set for further studies.

Computational Methods in Drug Discovery

“…Thr623 and Ser624 are thought to interact with the polar tails of some ligands and some evidence exists of a second 382 binding site (Aronov, 2005;Recanatini et al, 2005;Choe et al, 2006;Sanguinetti and Tristani-Firouzi, 2006). In vitro and in vivo methods are commonly used to evaluate drug candidates for potential hERG blockade activity, especially patch clamp techniques and radioligand binding assays (Wood et al, 2004;Polak et al, 2009). However, these methods are difficult to scale to high-throughput candidate evaluation, making the computational approach attractive for this aspect of drug discovery.…”

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

“…3 middle lower). The IC 50 values of the human ether-à-go-go-related gene (hERG) K + channel have been reported to be 7.2-10.7 for disopyramide, 262.9 for lidocaine and 3.9 μmol/L for flecainide at 35-37ºC (Polak et al, 2009), which may partly explain the difference in the extent of prolongation of field potential duration. It should be noted that the result for lidocaine was directionally different from that in the in situ human heart, in which the QT interval was shortened via late Na + current inhibition (Johannesen et al, 2016).…”

Strong Activation of ether-à-go-go-Related Gene 1 K+ Channel Isoforms by NS1643 in Human Embryonic Kidney 293 and Chinese Hamster Ovary Cells

“…This lower sensitivity is readily explained by the size of the oocytes and the presence of yolk particles (Witchel et al, 2002;Polak et al, 2009). Nevertheless, other mechanisms might contribute to the observed differences in the potency of NS1643 to shift erg1 channel activation.…”