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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular switch for CLC-K CI~- channel block/activation: Optimal pharmacophoric requirements towards high-affinity ligands
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Molecular switch for CLC-K CI~- channel block/activation: Optimal pharmacophoric requirements towards high-affinity ligands

机译：用于CLC-K CI〜-通道阻滞/激活的分子开关：对高亲和力配体的最佳药效学要求

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摘要

CIC-Ka and CIC-Kb CI~- channels are pivotal for renal salt reabsorp-tion and water balance. There is growing interest in identifying ligands that allow pharmacological interventions aimed to modulate their activity. Starting from available ligands, we followed a rational chemical strategy, accompanied by computational modeling and electrophysiological techniques, to identify the molecular requisites for binding to a blocking or to an activating binding site on CIC-Ka. The major molecular determinant that distinguishes activators from blockers is the level of planarity of the aromatic portions of the molecules: only molecules with perfectly coplanar aromatic groups display potentiating activity. Combining several molecular features of various CLC-K ligands, we discovered that phenyl-benzofuran carboxylic acid derivatives yield the most potent CIC-Ka inhibitors so far described (affinity < 10 μM). The increase in affinity compared with 3-phenyl-2-p-chlorophenoxy-propionic acid (3-phenyl-CPP) stems primarily from the conforma-tional constraint provided by the phenyl-benzofuran ring. Several other key structural elements for high blocking potency were identified through a detailed structure-activity relationship study. Surprisingly, some benzofuran-based drugs inhibit CIC-Kb with a similar affinity of <10 μM, thus representing the first inhibitors for this CLC-K isoform identified so far. Based on our data, we established a pharmacophore model that will be useful for the development of drugs targeting CLC-K channels.
机译：CIC-Ka和CIC-Kb CI〜-通道对于肾盐吸收和水平衡至关重要。对鉴定配体的兴趣日益浓厚，这些配体可以进行旨在调节其活性的药理学干预。从可用的配体开始，我们遵循合理的化学策略，再加上计算模型和电生理技术，以鉴定与CIC-Ka上的封闭位点或激活结合位点结合的分子条件。区分活化剂和阻滞剂的主要分子决定因素是分子芳族部分的平面度：只有具有完美共面芳族基团的分子才能显示出增强活性。结合各种CLC-K配体的几个分子特征，我们发现，苯基-苯并呋喃羧酸衍生物可产生迄今为止描述的最有效的CIC-Ka抑制剂（亲和力<10μM）。与3-苯基-2-对氯苯氧基丙酸（3-苯基-CPP）相比，亲和力的增加主要是由苯基-苯并呋喃环提供的构象约束。通过详细的结构-活性关系研究，确定了高封闭力的其他几个关键结构要素。出人意料的是，一些基于苯并呋喃的药物以<10μM的相似亲和力抑制CIC-Kb，从而代表了迄今为止确定的第一种CLC-K同工型抑制剂。根据我们的数据，我们建立了一个药效团模型，该模型将有助于开发针对CLC-K通道的药物。

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