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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.
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Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.

机译：布比卡因阻断hERG通道：立体化学优化的电生理学和建模见解。

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The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.
机译：hERG电压门控钾通道介导心脏I（Kr）电流，这对于心脏动作电位的持续时间至关重要。某些药物不希望的阻塞通道可能会延长QT间隔并增加恶性室性心律失常的风险。尽管已深入研究了hERG嵌段的分子决定因素，但对其立体选择性知之甚少。左旋（S）-布比卡因是第一种据报道比对映体对hERG具有更高亲和力的药物。这项研究致力于通过诱变分析和分子建模模拟来了解布比卡因嵌段立体选择性的基本原理。突变的hERG通道的电生理学测量值可用于确定与布比卡因结合和立体选择性有关的残基。布比卡因和特非那定的对映异构体（非立体选择性阻滞剂）的对接和分子力学模拟是在hERG通道的开放状态模型内进行的。预测的结合模式使配体-蛋白质相互作用的清晰描述。两种对映体的估计结合亲和力与电生理学测量结果一致。对两个突变的hERG通道（Tyr652Ala和Phe656Ala）的布比卡因对映体采用了类似的计算程序。这项研究在分子水平上证实了布比卡因立体选择性结合hERG通道。这些结果有助于为优化计算机候选药物的心脏毒性特征的结构指南奠定基础。

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