title: Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers.
abstract: 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.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
authors.forename: Alex M
authors.initials: AM
authors.lastname: Aronov
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D017294:Ondansetron / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; C076170:mizolastine; D017294:Ondansetron; D007654:Ketoconazole