Revealing Molecular Determinants of hERG Blocker and Activator Binding

The Kv11.1 potassium channel, encoded
by the human ether-a-go-go-related
gene (hERG), plays an essential role in the cardiac action potential.
hERG blockade by small molecules can induce “torsade de pointes”
arrhythmias and sudden death; as such, it is an important off-target
to avoid during drug discovery. Recently, a cryo-EM structure of the
open channel state of hERG was reported, opening the door to in silico
docking analyses and interpretation of hERG structure–activity
relationships, with a view to avoiding blocking activity. Despite
this, docking directly to this cryo-EM structure has been reported
to yield binding modes that are unable to explain known mutagenesis
data. In this work, we use molecular dynamics simulations to sample
a range of channel conformations and run ensemble docking campaigns
at the known hERG binding site below the selectivity filter, composed
of the central cavity and the four deep hydrophobic pockets. We identify
a hERG conformational state allowing discrimination of blockers vs
nonblockers from docking; furthermore, the binding pocket agrees with
mutagenesis data, and blocker binding modes fit the hERG blocker pharmacophore.
We then use the same protocol to identify a binding pocket in the
hERG channel pore for hERG activators, again agreeing with the reported
mutagenesis. Our approach may be useful in drug discovery campaigns
to prioritize candidate compounds based on hERG liability via virtual
docking screens.