Ring Size as an Independent Variable in Cyclooligomeric Depsipeptide Antiarrhythmic Activity.
Ring Size as an Independent Variable in Cyclooligomeric Depsipeptide Antiarrhythmic Activity.
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DOI：
10.1021/acsmedchemlett.1c00508
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发表时间：
2021-11
影响因子：
4.2
通讯作者：
Abigail N. Smith;Daniel J. Blackwell;B. Knollmann;J. Johnston
中科院分区：
文献类型：
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作者：
Abigail N. Smith;Daniel J. Blackwell;B. Knollmann;J. Johnston
命中-先导研究采用多种策略来优化与感兴趣的靶标的结合。当靶点的结构可用时，假设驱动的结构-活性关系（SAR）是一种强大的策略，用于精炼药效团，以实现识别先导化合物所需的强大结合和选择性特征。改造小分子占据的三维空间、优化氢键接触和增强局部吸引相互作用是药物化学中的传统方法。然而，环的大小很少能够作为一个独立的变量，因为大多数命中缺乏对称性所需的这样一个研究。我们的发现，环状寡聚缩酚肽ent-verticilide抑制哺乳动物心脏ryanodine受体钙释放通道亚微摩尔效力提供了一个机会，探索环大小作为一个变量，独立于其他结构或官能团的变化。我们在这里报告说，环的大小可以是一个关键的自变量，这表明，温和的构象变化单独可以显着影响效力。
Hit-to-lead studies employ a variety of strategies to optimize binding to a target of interest. When a structure for the target is available, hypothesis-driven structure-activity relationships (SAR) are a powerful strategy for refining the pharmacophore to achieve robust binding and selectivity characteristics necessary to identify a lead compound. Recrafting the three-dimensional space occupied by a small molecule, optimization of hydrogen bond contacts, and enhancing local attractive interactions are traditional approaches in medicinal chemistry. Ring size, however, is rarely able to be leveraged as an independent variable because most hits lack the symmetry required for such a study. Our discovery that the cyclic oligomeric depsipeptide ent-verticilide inhibits mammalian cardiac ryanodine receptor calcium release channels with submicromolar potency provided an opportunity to explore ring size as a variable, independent of other structural or functional group changes. We report here that ring size can be a critical independent variable, suggesting that modest conformational changes alone can dramatically affect potency.