Key result
Bulky propafenone derivatives fit within the hERG cavity without disrupting channel gate closure.
Why the study?
Inhibition of hERG K+ channels prolongs the ventricular action potential and increases the risk of torsade de pointes and sudden cardiac death, and drug trapping behind closed channel gates is suggested to harbor an increased pro-arrhythmic risk.
Electrophysiological and molecular dynamics simulations demonstrate that the hERG channel cavity can accommodate very bulky compounds without disturbing gate closure, which has implications for understanding drug-induced arrhythmias.
Inhibition of hERG K+ channels by structurally diverse drugs prolongs the ventricular action potential and increases the risk of torsade de pointes arrhythmias and sudden cardiac death. The capture of drugs behind closed channel gates, so-called drug trapping, is suggested to harbor an increased pro-arrhythmic risk. In this study, the trapping mechanisms of a trapped hERG blocker propafenone and a bulky derivative (MW: 647.24 g mol-1) were studied by making use of electrophysiological measurements in combination with molecular dynamics simulations. Our study suggests that the hERG cavity is able to accommodate very bulky compounds without disturbing gate closure.
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Linder et al. (2015) studied hERG K+ channel drug trapping / drug-induced torsade de pointes arrhythmia. Propafenone and a bulky derivative (MW: 647.24 g mol-1) was evaluated on Drug trapping mechanism and gate closure in hERG K+ channels. Propafenone and a bulky derivative (MW 647.24 g/mol) were accommodated within the hERG K+ channel cavity without disturbing gate closure during drug trapping.
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