title: Computer simulations of structure-activity relationships for HERG channel blockers.
abstract: The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causing serious cardiac side effects, is a major problem in drug development. Despite the large amounts of existing biochemical data on blockade of hERG by drugs and druglike compounds, relatively little is known regarding the structural basis of binding of blockers to the channel. Here, we have used a recently developed homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations yield a remarkably good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships in terms of a number of key interactions. Two main interaction regions of the channel are thus identified with implications for further mutagenesis experiments and design of new compounds.
authors.affiliation: Department of Cell and Molecular Biolog, Uppsala University , Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Boukharta
authors.forename: Henrik
authors.initials: H
authors.lastname: Keränen
authors.forename: Anna
authors.initials: A
authors.lastname: Stary-Weinzinger
authors.forename: Göran
authors.initials: G
authors.lastname: Wallin
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects; D015203:Reproducibility of Results; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D007211:Indoles; C496884:KCNH1 protein, human; D008024:Ligands; D026902:Potassium Channel Blockers; C066304:sertindole