title: Modeling of high-affinity binding of the novel atrial anti-arrhythmic agent, vernakalant, to Kv1.5 channels.
abstract: Vernakalant (RSD1235) is an investigational drug that converts atrial fibrillation rapidly and safely in patients intravenously [Roy et al., J. Am. Coll. Cardiol. 44 (2004) 2355-2361; Roy et al., Circulation 117 (2008) 1518-1525] and maintains sinus rhythm when given orally [Savelieva et al., Europace 10 (2008) 647-665]. Here, modeling using AutoDock4 allowed exploration of potential binding modes of vernakalant to the open-state of the Kv1.5 channel structure. Point mutations were made in the channel model based on earlier patch-clamp studies [Eldstrom et al., Mol. Pharmacol. 72 (2007) 1522-1534] and the docking simulations re-run to evaluate the ability of the docking software to predict changes in drug-channel interactions. Each AutoDock run predicted a binding conformation with an associated value for free energy of binding (FEB) in kcal/mol and an estimated inhibitory concentration (K(i)). The most favored conformation had a FEB of -7.12 kcal/mol and a predicted K(i) of 6.08 microM (the IC50 for vernakalant is 13.8 microM; [Eldstrom et al., Mol. Pharmacol. 72 (2007) 1522-1534]). This conformation makes contact with all four T480 residues and appears to be clearly positioned to block the channel pore.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Jodene
authors.initials: J
authors.lastname: Eldstrom
authors.forename: David
authors.initials: D
authors.lastname: Fedida
mesh_terms: D000595:Amino Acid Sequence; D000840:Anisoles / Q000737:chemistry* / Q000378:metabolism*; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D011759:Pyrrolidines; C524581:vernakalant