Modeling of high-affinity binding of the novel atrial anti-arrhythmic agent, vernakalant, to Kv1.5 channels.

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.