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Inhibition of Voltage-Gated K+ Channel Kv1.5 by Antiarrhythmic Drugs

机译：抑制电压门控K + / sup>通道Kv1.5通过抗真菌药物

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摘要

Molecular dynamics simulations are employed to determine the inhibitory mechanisms of three drugs, 5-(4-phenoxybutoxy)psoralen (PAP-1), vernakalant, and flecainide, on the voltage-gated K~(+) channel Kv1.5, a target for the treatment of cardiac arrhythmia. At neutral pH, PAP-1 is neutral, whereas the other two molecules carry one positive charge. We show that PAP-1 forms stable dimers in water, primarily through hydrophobic interactions between aromatic rings. All three molecules bind to the cavity between the Ile508 and Val512 residues from the four subunits of the channel. Once bound, the drug molecules are flexible, with the average root-mean-square fluctuation being between 2 and 3 ?, which is larger than the radius of gyration of a bulky amino acid. The presence of a monomeric PAP-1 causes the permeating K~(+) ion to dehydrate, thereby creating a significant energy barrier. In contrast, vernakalant blocks the ion permeation primarily via an electrostatic mechanism and, therefore, must be in the protonated and charged form to be effective.
机译：用于测定三种药物，5-（4-苯氧基丁氧基）（PAP-1），vernakalant和絮状物的抑制机制，在电压门控K〜（+）通道Kv1.5，靶标用于治疗心律失常。在中性pH下，PAP-1是中性的，而另外两种分子载有一个正电荷。我们表明PAP-1在水中形成稳定的二聚体，主要通过芳环之间的疏水相互作用。所有三个分子与来自通道的四个亚基的ILE508和VAL512残基之间的腔结合。一旦结合，药物分子是柔性的，平均根部平均方波动在2和3之间？，其大于庞大氨基酸的环状半径。单体PAP-1的存在使渗透k〜（+）离子脱水，从而产生显着的能量屏障。相反，vernakalant主要通过静电机构阻塞离子渗透，因此必须处于质子化和带电形式以有效。

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  • 来源
    《Biochemistry》 |2018年第18期|共7页
  • 作者

    Rong Chen; Shin-Ho Chung;

  • 作者单位

    Research School of Biology Australian National University Acton ACT 2601 Australia;

    Research School of Biology Australian National University Acton ACT 2601 Australia;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
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