The study proposes a novel pharmacophore model to predict and eliminate hERG channel blockade liability in uncharged chemical series.
In silico approaches are widely used to predict human ether-a-go-go-related gene (hERG) channel blockade. Published pharmacophore models of hERG blockers typically contain a basic nitrogen center flanked by aromatic or hydrophobic groups. However, hERG blockade has been observed in series lacking the basic nitrogen. By utilizing screening data for 194 potent uncharged hERG actives, we propose a pharmacophore for neutral hERG blockers, and provide guidance on eliminating hERG liability in an uncharged hERG active chemical series.
Alex M. Aronov (Wed,) studied this question.