Key result
Molecular dynamics simulations identify a hERG conformational state discriminating blockers from nonblockers and locating activator pockets.
Why the study?
Direct docking to the open-state hERG cryo-EM structure yields binding modes unable to explain known mutagenesis data, despite hERG blockade being a critical off-target risk.
Molecular dynamics simulations identified hERG channel conformations that accurately discriminate between blockers and nonblockers, providing a useful tool for virtual docking screens in drug discovery to avoid arrhythmogenic liabilities.
May aid virtual screening to reduce hERG-related arrhythmia risk in drug discovery; leaves open experimental validation before clinical use.
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.
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Dickson et al. (2019) studied hERG blockade and arrhythmias. Molecular dynamics simulations and ensemble docking was evaluated on Identification of hERG conformational states for blocker and activator binding. Molecular dynamics simulations and ensemble docking identified a hERG conformational state that discriminates blockers from nonblockers and locates a binding pocket for hERG activators.
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