连接体硫氧化状态逐渐改变galactin-3-连接体复合体的构造,以诱导影响亲和关系的键
Mukul Mahanti1, Kumar Bhaskar Pal1, Rohit Kumar2
1Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
Journal of medicinal chemistry
|October 25, 2023
概括
研究人员通过改变硫氧化状态来修改了galectin-3配体. 硫衍生物通过多个键显著增强了结合亲和力,影响了免疫调节和瘤进展研究.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药用化学 医学化学
背景情况:
- galectins,特别是 galectin-3,对于免疫调节和瘤进展至关重要.
- 高亲和性对甲基-3的配体通常涉及银河糖核和甲酸部分,利用疏水和π堆叠相互作用.
研究的目的:
- 设计和合成具有不同硫氧化状态 (硫化物,硫氧化物,硫) 的新型硫酸衍生物.
- 调查这些结构修改如何影响连接体结合亲和力和与加勒-3的相互作用模式.
- 探索结,疏水性和π相互作用对联结蛋白复合体结构和热力学的影响.
主要方法:
- 硫,硫氧化物和硫化物-三烯基甲酸衍生物的化学合成.
- 用X射线晶体学来确定连接体-蛋白质复合体的结构.
- 热力学分析 (例如,异热定位热量计) 用于量化结合亲和和和能量.
主要成果:
- 硫氧化物和硫联体形成键,同时保持π相互作用,导致改变结合姿势和改善亲缘关系.
- 与硫化物相比,硫氧化物衍生物的亲和力降低.
- 硫衍生物形成了三个键 (两个直接,一个通过水介导),显著增加了结合亲和力,并改变了复杂的结构.
结论:
- 硫的氧化状态在triozolyl thiogalactoside衍生品中批判性地调节了与 galectin-3 的相互作用.
- 增强的键,特别是在硫衍生物中,是增加结合亲和力和改变复合物形成的关键.
- 这些发现为在免疫和癌症生物学中的治疗应用设计强效的加勒-3抑制剂提供了洞察力.
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