Structural modeling of hERG channel: Drug interactions using Rosetta

Human Ether-a-go-go-Related Gene (hERG) encodes a potassium-selective
voltage-gated ion channel essential for normal electrical activity in the
heart but is also a major drug anti-target. Genetic hERG mutations and
blockage of the channel pore by drugs can cause long QT syndrome (LQTS),
which predisposes individuals to potentially deadly arrhythmias. 
However, not all hERG blocking drugs are pro-arrhythmic, and their
differential affinities to discrete channel conformational states have
been suggested to contribute to arrhythmogenicity. We used Rosetta
electron density refinement and homology modeling to build structural
models of open-state hERG channel wild-type (WT) and mutant variants
(Y652A, F656A, and Y652A/F656A), and a closed state WT channel based on
cryo-electron microscopy structures of hERG and EAG1 channels. These
models were used as protein targets for molecular docking of charged and
neutral forms of amiodarone, nifekalant, dofetilide, d/l-sotalol,
flecainide, and moxifloxacin. We selected these drugs based on their
different arrhythmogenic potentials and abilities to facilitate hERG
current. Our docking studies and clustering provided atomistic structural
insights into state-dependent drug–channel interactions l that play a key
role in differentiating safe and harmful hERG blockers and can explain
hERG channel facilitation through drug interactions with its open-state
hydrophobic pockets.