title: Screening for Non-Pore-Binding Modulators of EAG K+ Channels.
abstract: Members of the ether-à-go-go (EAG) family of voltage-gated K(+) channels are involved in several pathophysiological diseases, and there has been a great interest in screening for drugs that modulate the activity of these channels. Many drugs have been shown to bind in the pore of these channels, blocking ion flux and causing disease pathology. In this report, we present two independent screening campaigns in which we wanted to identify small molecules that bind to either the intracellular cytoplasmic amino terminal Per-Arnt-Sim (PAS) domain from the human EAG-related gene (ERG) channel or the amino or carboxy terminal globular domains from the mouse EAG1 channel, affecting their interaction. We report that in both cases, compounds were identified that showed weak, nonspecific binding. We suggest alternative routes should be pursued in future efforts to identify specific, high-affinity binders to these cytoplasmic domains.
authors.affiliation: IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Andreia S
authors.initials: AS
authors.lastname: Fernandes
authors.affiliation: IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: João H
authors.initials: JH
authors.lastname: Morais-Cabral
authors.affiliation: IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal harleyca@ibmc.up.pt.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Harley
mesh_terms: D000818:Animals; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D051379:Mice; D000072417:Protein Domains / Q000187:drug effects; D017434:Protein Structure, Tertiary
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human
keywords: CNBh; EAG1; PAS; drug screening; hERG; ion channel