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. 2016 Mar 1;7(3):512-518.
doi: 10.1039/c5md00443h. Epub 2015 Dec 22.

Drug trapping in hERG K+ channels: (not) a matter of drug size?

Tobias Linder  1 , Harald Bernsteiner  1 , Priyanka Saxena  1 , Florian Bauer  2 , Thomas Erker  2 , Eugen Timin  1 , Steffen Hering  1 , Anna Stary-Weinzinger  1
Affiliations

Drug trapping in hERG K+ channels: (not) a matter of drug size?

Tobias Linder et al. Medchemcomm. .

Abstract

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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Figures

Fig. 1
Fig. 1. WT hERG channels inhibition by Fb213. (A) Chemical structure of FB213; (B) voltage pulse protocol shown; (C) superimposed current traces recorded in the absence (control) and after attaining a steady-state block with increasing concentrations of FB213 at 0.3 Hz; (D) the concentration–response relationship for the block of the hERG tail current by FB213; (E) superimposed current traces of the first (control, black) and last (‘steady-state block’, green) pulses during a conditioning train of 1 Hz after application of 150 μM FB213 Recovery current from the FB213 block in the continued presence of drug at rest, resulting from a single test pulse after 330 s resting time is depicted as red, washout of the FB213 block is shown in blue; (F) mean normalized peak tail current amplitudes in the presence of 150 μM FB213 is plotted against time. The section ‘block’ shows the development of inhibition during a 1 Hz pulse train. The grey highlighted section ‘recovery’ maps the amount of recovery after a 330 s resting time; (G) repetitive stimulation accelerates wash-out of FB213. The hERG channels were inhibited by a 1 Hz pulse train, as described in Fig. 1F. After reaching steady state of inhibition, the drug was washed out. During the wash-out process, pulses were applied at 0.3 Hz frequency. Peak tail currents were normalized to control the currents (amplitude before drug application) and plotted against time.
Fig. 2
Fig. 2. FB213 interacts with binding sites Y652 and F656. (A, B) Representative current traces and corresponding voltage protocols for current measurements of mutants Y652A and F656A in the absence (control) and presence of FB213, respectively. The tail currents of F656A were recorded at –140 mV. (C) Normalized peak tail currents of WT, Y652A, and F656A channels after the steady state block by 150 μM FB213 (n = 4, error bars, ± SEM).
Fig. 3
Fig. 3. Modelling of FB213 trapping. (A) Bottom view of FB213 (yellow spheres) docked into the open state hERG model. (B) Side view of FB213 interactions with the aromatic side chains of Y652 and F656. Hydrogen bonds are depicted as green dotted lines. (C) Bottom view of the trapped FB213 after 20 ns ED simulations. (D) Side view of the compound in the closed state.
Fig. 4
Fig. 4. Modelling of propafenone trapping. (A) Bottom view of propafenone shown in yellow spheres docked into the open state hERG model. (B) Side view of propafenone interactions with the side chains of Y652, F656 and S624. Hydrogen bonds are depicted as green dotted lines. (C) Bottom view of the trapped propafenone molecule after 20 ns ED simulations. (D) Side view of the compound in the closed state.
Fig. 5
Fig. 5. Analysis of rotameric states of F656. (A–B) Down states are defined by χ1 angles ≤123°. The percentage of the down state was calculated for each time step and plotted over time averaged over 5 trapping runs/drug.
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