An exploration of interactions between the antiarrhythmic drug dronedarone and hERG potassium channel pore

Abstract

Dronedarone is a non-iodinated analogue of the Class III antiarrhythmic agent amiodarone. It exerts potent inhibition of "hERG" potassium channels that underpin the cardiac rapid delayed rectifier potassium current, IKr. This study aimed to extend understanding of interactions between dronedarone and the hERG channel. Whole-cell patch-clamp recordings were made at 37C of hERG channel current (IhERG) from HEK-293 cells expressing wild-type (WT) hERG or alanine mutants of residues in the channel's pore-helix/selectivity filter region (T623, S624, V625) or S6 helices (S649, Y652, F656, V659). Molecular docking simulations were performed using a cryo-EM structure of hERG and a MthK-based homology model. The half-maximal inhibitory (IC50) value for WT IhERG inhibition by dronedarone was 42.6 ± 3.9 nM (n= at least 5 cells for each of 6 concentrations). 600 nM dronedarone exerted reduced WT IhERG block when the direction of K + flux was reversed, consistent with interactions between the drug and permeant ion. In contrast with recently reported data for amiodarone, the S624A mutation did not attenuate IhERG blockade, whilst T623A and V625A channels exhibited modestly attenuated block. The S649A mutation was without significant effect and the Y652A and F656A mutations exhibited modest reductions in block. The V659A mutation produced the most marked effect on dronedarone action. Docking simulations were generally consistent with modest interactions with canonical binding residues and suggested an indirect rather than direct effect of the V659A mutation on the drug's action. These findings leave open the possibility that as yet unexplored residue(s) could act as key determinants of high affinity hERG channel block by dronedarone.