Global analysis reveals families of chemical motifs enriched for hERG inhibitors

Fang Du, Joseph J. Babcock, Haibo Yu, Beiyan Zou, Min Li

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere0118324
JournalPloS one
Volume10
Issue number2
DOIs
StatePublished - Feb 20 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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