Prediction of hERG K+ blocking potency: application of structural knowledge

SAR QSAR Environ Res. 2004 Oct-Dec;15(5-6):399-411. doi: 10.1080/10629360412331297353.

Abstract

Modelling of QT-prolongation has been performed using data for 19 structurally diverse hERG K+ channel blocking drugs taken from literature. The modelling used hydrophobicity corrected for ionisation (log D) and various 2D and 3D physico-chemical molecular descriptors. Stepwise regression produced a two parameter, interpretable and transparent QSAR with good statistical fit, including log D and the maximum diameter of molecules (Dmax). Two strategies were applied for model validation: (i) a scrambling procedure, i.e., training the total set of 19 chemicals after randomising the hERG K+ channel blocking activity data and (ii) use of external validation sets. Validation of the models showed them to be stable and statistically significant. The effect of molecular size on QT-prolongation side effect is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Arrhythmia Agents / chemistry*
  • Anti-Arrhythmia Agents / pharmacology
  • Hydrophobic and Hydrophilic Interactions
  • Inhibitory Concentration 50
  • Knowledge
  • Models, Biological
  • Molecular Conformation
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels, Voltage-Gated / antagonists & inhibitors*
  • Potassium Channels, Voltage-Gated / metabolism
  • Predictive Value of Tests*
  • Quantitative Structure-Activity Relationship
  • Regression Analysis

Substances

  • Anti-Arrhythmia Agents
  • Potassium Channel Blockers
  • Potassium Channels, Voltage-Gated