Molecular Origins of State-Dependent Herg1 Blockade by Dofetilide

Abstract

Dofetilide is an antiarrhythmic agent used for the maintenance and protection of sinus rhythm from atrial fibrillations and flutters in individuals. However, dofetilide is better known for its arrhythogenic activity and blockade of IKr currents and is limited in clinical use. An inadvertent drug blockade of hERG channel predisposes to drug-induced Long-QT2 syndrome in humans. It is well established that dofetilide reversibly binds with moderate-to-high affinity to an open state of hERG1 reversibly but irreversibly blocks open-inactivated state. Here, we used a combination of MD simulations and free energy simulations to unravel key determinants of state-dependent blockade of hERG1. It was found that inactivation of the channel and formation of open-inactivate state of hERG1 leads to narrowly localized high-affinity binding pocket for dofetilide. The corresponding Potential of Mean Force (PMF) for drug dissociation from open state of the channel is markedly different. It shows shallow but broad minima. To place findings from atomistic simulations to cellular context we performed kinetic modeling of IKr currents using Markov-net models developed previously. The results were compared to electrophysiological recordings of dofetilide binding to WT and 656C mutants of hERG1 channel.