Revealing Molecular Determinants of hERG Blocker and Activator Binding

Abstract

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.

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

“…It is widely assumed that bound hERG blockers are fully buried within the pore domain based on mutagenesis data and in silico docking [30,31], which we had likewise assumed in our previous work [24]. However, this hypothesis is inconsistent with the large size/volume of many blockers, wherein binding would likely depend on an unreasonably high level of induced fit.…”

In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel—A Drug Antitarget

“…The F656 residue is well-known to be an important determinant of drug-hERG channel interactions and its position relative to pore varies between models ( 41 ). The published Dickson model was obtained from MD simulations in the presence of hERG inhibitors ( 42 ). The in-house model was obtained from a short MD simulation in which the F656 side chain of one of the four hERG subunits was found to reorient toward the pore—this subunit was then replicated around all four pore subunits to produce a model with all four F656 side chains facing the pore.…”

Electrophysiological characterization of the modified hERG T potassium channel used to obtain the first cryo‐EM hERG structure

“…It seems unlikely that this small difference would result in large conformational differences between the pore of WT and hERG T channels. Thus, it seems more likely that the cryo‐EM structure captured a low affinity open state in which the positions of binding residues are nonoptimally configured for interaction with some drugs (Helliwell et al., 2018), although recent studies indicate that the energetic barriers to reorientation of Phe side chains into configurations more optimal for interaction with drugs may be small (Dickson, Velez‐Vega, & Duca, 2020; Negami, Araki, Okuno, & Terada, 2019). There are only limited data available on the pharmacology of hERG T channels (Wang & MacKinnon, 2017) and, with the properties of hERG T I hERG now more fully characterized, we suggest that future comparison be made of effects on drug binding of mutations to key binding residues in the canonical drug binding between WT and hERG T .…”