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

J Appl Toxicol. 2009 Apr;29(3):183-206. doi: 10.1002/jat.1395.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods*
  • ERG1 Potassium Channel
  • Electrophysiology
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Ether-A-Go-Go Potassium Channels / physiology
  • Humans
  • Inhibitory Concentration 50
  • Long QT Syndrome / chemically induced
  • Long QT Syndrome / physiopathology
  • Models, Cardiovascular
  • Potassium Channel Blockers / adverse effects
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Quantitative Structure-Activity Relationship
  • Risk Assessment
  • Torsades de Pointes / chemically induced
  • Torsades de Pointes / physiopathology

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Potassium Channel Blockers