title: Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods.
abstract: Binding of blockers to the human voltage-gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Osterberg
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
mesh_terms: D000595:Amino Acid Sequence; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated