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Issue 3, 2016
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Drug trapping in hERG K+ channels: (not) a matter of drug size?

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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.

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

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Supplementary files

Article information


Submitted
02 Oct 2015
Accepted
18 Dec 2015
First published
22 Dec 2015

This article is Open Access

Med. Chem. Commun., 2016,7, 512-518
Article type
Research Article

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

T. Linder, H. Bernsteiner, P. Saxena, F. Bauer, T. Erker, E. Timin, S. Hering and A. Stary-Weinzinger, Med. Chem. Commun., 2016, 7, 512 DOI: 10.1039/C5MD00443H

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