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.

中文翻译：

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hERG K+ 通道中的药物捕获：（不是）药物大小的问题？


结构不同的药物抑制 hERG K+ 通道会延长心室动作电位，并增加尖端扭转性心律失常和心源性猝死的风险。在封闭的通道门后捕获药物，即所谓的药物捕获，被认为会增加致心律失常的风险。在本研究中，通过电生理测量与分子动力学模拟相结合，研究了被捕获的 hERG 阻滞剂普罗帕酮和大体积衍生物（MW：647.24 g mol-1）的捕获机制。我们的研究表明，hERG 腔能够容纳非常大的化合物，而不会干扰门的关闭。