title: Dynamics of hERG closure allow novel insights into hERG blocking by small molecules.
abstract: Today, drug discovery routinely uses experimental assays to determine very early if a lead compound can yield certain types of off-target activity. Among such off targets is hERG. The ion channel plays a primordial role in membrane repolarization and altering its activity can cause severe heart arrhythmia and sudden death. Despite routine tests for hERG activity, rather little information is available for helping medicinal chemists and molecular modelers to rationally circumvent hERG activity. In this article novel insights into the dynamics of hERG channel closure are described. Notably, helical pairwise closure movements have been observed. Implications and relations to hERG inactivation are presented. Based on these dynamics novel insights on hERG blocker placement are presented, compared to literature, and discussed. Last, new evidence for horizontal ligand positioning is shown in light of former studies on hERG blockers.
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 87290 Croissy-sur-Seine, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidtke
authors.forename: Marine
authors.initials: M
authors.lastname: Ciantar
authors.forename: Isabelle
authors.initials: I
authors.lastname: Theret
authors.forename: Pierre
authors.initials: P
authors.lastname: Ducrot
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport; D051663:Kv1.2 Potassium Channel / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010627:Phenethylamines / Q000737:chemistry* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D051669:Shab Potassium Channels / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496988:KCNB1 protein, human; C000606913:KCNH2 protein, human; D051663:Kv1.2 Potassium Channel; D008024:Ligands; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011993:Recombinant Fusion Proteins; D051669:Shab Potassium Channels; D054852:Small Molecule Libraries; D013449:Sulfonamides; C063533:dofetilide