Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium

Area of Science:

• Cardiovascular Pharmacology
• Molecular Biophysics
• Computational Chemistry

Background:

• The binding modes of most human Ether-a-go-go-Related Gene (hERG) ion channel blockers are understood.
• Clofilium, a potent antiarrhythmic agent, is an exception, with its hERG channel blocking mechanism not fully elucidated.
• Previous hypotheses on clofilium's binding to hERG could not fully explain experimental data.

Purpose of the Study:

• To analyze hypothesized binding modes of clofilium to the hERG channel using computer simulations.
• To identify the consensus binding mode of clofilium.
• To provide a novel explanation for clofilium's potency and its interaction with related channels.

Main Methods:

• Utilized molecular dynamics (MD) simulations.
• Employed interaction energy calculations.
• Analyzed binding modes through computational modeling.

Main Results:

• An unexpected binding mode for clofilium was identified.
• The quaternary nitrogen of clofilium strongly interacts with Ser624 in the upper cavity.
• The chlorophenyl group is positioned in the lower cavity, aligning with prior experimental findings.

Conclusions:

• The novel binding mode explains clofilium's higher affinity for the related hEag1 channel.
• Potent hERG blockers may interact uniquely with residues near the intracellular activation gate.
• This research offers a new framework for predicting the potency of other hERG-blocking compounds.