Global analysis reveals families of chemical motifs enriched for HERG inhibitors

PLoS One. 2015 Feb 20;10(2):e0118324. doi: 10.1371/journal.pone.0118324. eCollection 2015.

Abstract

Promiscuous inhibition of the human ether-à-go-go-related gene (hERG) potassium channel by drugs poses a major risk for life threatening arrhythmia and costly drug withdrawals. Current knowledge of this phenomenon is derived from a limited number of known drugs and tool compounds. However, in a diverse, naïve chemical library, it remains unclear which and to what degree chemical motifs or scaffolds might be enriched for hERG inhibition. Here we report electrophysiology measurements of hERG inhibition and computational analyses of >300,000 diverse small molecules. We identify chemical 'communities' with high hERG liability, containing both canonical scaffolds and structurally distinctive molecules. These data enable the development of more effective classifiers to computationally assess hERG risk. The resultant predictive models now accurately classify naïve compound libraries for tendency of hERG inhibition. Together these results provide a more complete reference map of characteristic chemical motifs for hERG liability and advance a systematic approach to rank chemical collections for cardiotoxicity risk.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cardiotoxicity
  • Cricetinae
  • Cricetulus
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Potassium Channel Blockers / adverse effects
  • Potassium Channel Blockers / chemistry*
  • Potassium Channel Blockers / pharmacology
  • Protein Binding
  • Small Molecule Libraries / adverse effects
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology

Substances

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