title: Homology modeling of Kv1.5 channel block by cationic and electroneutral ligands.
abstract: The inner pore of potassium channels is targeted by many ligands of intriguingly different chemical structures. Previous studies revealed common and diverse characteristics of action of ligands including cooperativity of ligand binding, voltage- and use-dependencies, and patterns of ligand-sensing residues. Not all these data are rationalized in published models of ligand-channel complexes. Here we have used energy calculations with experimentally defined constraints to dock flecainide, ICAGEN-4, benzocaine, vernakalant, and AVE0118 into the inner pore of Kv1.5 channel. We arrived at ligand-binding models that suggest possible explanations for different values of the Hill coefficient, different voltage dependencies of ligands action, and effects of mutations of residues in subunit interfaces. Two concepts were crucial to build the models. First, the inner-pore block of a potassium channel requires a cationic "blocking particle". A ligand, which lacks a positively charged group, blocks the channel in a complex with a permeant ion. Second, hydrophobic moieties of a flexible ligand have a tendency to bind in hydrophobic subunit interfaces.
authors: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia. Electronic address: denistikhonov2002@yahoo.com.
authors: Denis B
authors: DB
authors: Tikhonov
authors: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Boris S
authors: BS
authors: Zhorov
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000840:Anisoles / Q000494:pharmacology; D001566:Benzocaine / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: C501729:AVE 0118; D000779:Anesthetics, Local; D000840:Anisoles; D001713:Biphenyl Compounds; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D011759:Pyrrolidines; D061567:Voltage-Gated Sodium Channel Blockers; C524581:vernakalant; D005424:Flecainide; D001566:Benzocaine
keywords: Channel block; Molecular modeling; Potassium channel