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Bioorg Med Chem Lett. 2013 Aug 15;23(16):4587-90. doi: 10.1016/j.bmcl.2013.06.034. Epub 2013 Jun 20.

Are hERG channel blockers also phospholipidosis inducers?

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National Center for Advancing Translational Sciences, National Institutes of Health (NIH), 9800 Medical Center Drive, Bethesda, Rockville, MD 20892, USA.


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.


Phospholipidosis; hERG; qHTS

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