TY - JOUR
AR - JICOA-2018-1-102
TI - An exploration of interactions between the antiarrhythmic drug dronedarone and hERG potassium channel pore
AU -  Christopher E. , Dempsey
AU - Charlotte K. , Colenso
AU - Jules , Hancox
AU - Yihong, Zhang
JO - Journal of Integrative Cardiology Open Access
PY - 2018
DA - Fri 31, Aug 2018
SN - 2674-2489
DO - http://dx.doi.org/10.31487/j.JICOA.2018.01.002
UR - https://www.sciencerepository.org/an-exploration-of-interactions-between-the-antiarrhythmic-drug-dronedarone-and-hERG-potassium-channel-pore_JICOA-1-102 
KW - Amiodarone, antiarrhythmic, Class III, Dronedarone, hERG, QT interval, potassium channel
AB - 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.