title: Are hERG channel blockers also phospholipidosis inducers?
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.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health (NIH), 9800 Medical Center Drive, Bethesda, Rockville, MD 20892, USA. sunh7@mail.nih.gov
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Sampada A
authors.initials: SA
authors.lastname: Shahane
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008064:Lipidoses / Q000139:chemically induced*; D015394:Molecular Structure; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D011395:Promazine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013256:Steroids / Q000737:chemistry
chemical_list: D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D010743:Phospholipids; D013256:Steroids; D011395:Promazine
keywords: Phospholipidosis; hERG; qHTS