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分子设计和系统优化素结合系统的喘中介素-5受体及其循环联体之间的素结合系统

Quan He¹, Shuanglan Xu², Xiaomei Ma¹

¹Department of Respiratory and Critical Care Medicine, Zhenjiang Hospital of Integrated Traditional Chinese and Western Medicine, Zhenjiang, China.

Chemical biology & drug design

|November 5, 2023

概括

这项研究通过引入素键来增强人类互白素-5 (IL-5) 的抑制剂 (AF17121). 优化的基酸显示显著改善了对IL-5受体α的结合亲和力,为喘提供了新的治疗潜力.

科学领域:

生物化学生物化学
结构生物学结构生物学
药用化学医学化学

背景情况:

人间白内素-5 (IL-5) 是一种促炎性细胞因子,涉及喘病因.
IL-5受体α (IL-5Rα) 是治疗干预的关键标.
之前已经确定了一种循环,AF17121,可以抑制IL-5Rα/IL-5相互作用.

研究的目的:

研究AF17121与IL-5Rα结合的结构和能量基础.
设计和合成具有增强结合亲和力的新型原型AF17121类似物.
探索素键在受体相互作用中的作用.

主要方法:

确定IL-5Rα与AF17121.1复合的晶体结构.
量子力学/分子力学 (QM/MM) 计算用于素键形成的理论分析.
在AF17121.1,AF17121.的基部分进行系统的基替代.
结合亲和度测试用于评估改性.

主要成果:

在IL-5Rα³EXXR⁶基因内,AF17121 Trp5残基的醇部分对IL-5Rα³EXXR⁶基因的相互作用至关重要.
QM/MM计算预测了环在环的5和6位置的有效素键.
基 [5I]AF17121 和 [6Br]AF17121 的结合亲和力分别提高了 1.6 倍和 3.5 倍.
[5I/6Br]AF17121的结合亲和力增加了7.5倍.
6-替代形成了一个协同作用的素键和键相互作用.

结论:

素结合是一种可行的策略,可以提高IL-5Rα抑制剂的效力.
优化AF17121的化导致显著改善的亲和力.
素和键的协同相互作用为向IL-5Rα的药物设计提供了一个有希望的方法.

关键词:

AF17121 一个有趣的故事在IL-5中,IL-5是最常见的.它们的IL-5Rα.喘喘是一种素键是一种素键.分子设计分子设计.这是一种类.

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