Are hERG channel blockers also phospholipidosis inducers?

Paradigms and Technologies

Abstract

Both pharmacophore models of the human ether-à-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/positively charged center, so it is interesting to investigate the overlap between the ligand chemical spaces of both targets. We have assayed over 4000 non-redundant drug-like compounds for both their hERG inhibitory activity and PLD inducing potential in a quantitative high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compounds identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compounds were positively charged. Among the 48 compounds that induced PLD without inhibiting hERG channel, 24 compounds (50.0%) carried steroidal structures. According to our results, hERG channel blockers and PLD inducers share a large chemical space. In addition, a positively charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.

Authors

Sun, Hongmao; Xia, Menghang; Shahane, Sampada A; Jadhav, Ajit; Austin, Christopher; Huang, Ruili;

Keywords

  • Antipsychotic Agents/ chemistry
  • Antipsychotic Agents/ pharmacology
  • Ether-A-Go-Go Potassium Channels/ antagonists & inhibitors
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipidoses/ chemically induced
  • Molecular Structure
  • Phospholipids/ chemistry
  • Phospholipids/ metabolism
  • Promazine/ chemistry
  • Promazine/ metabolism
  • Promazine/ pharmacology
  • Quantitative Structure-Activity Relationship
  • Steroids/ chemistry

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