在水和性溶剂中模仿三β链的形状受约束的宏循环
Robert C Reid1, Michael J Kelso, Martin J Scanlon
1Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.
Journal of the American Chemical Society
|May 16, 2002
概括
研究人员创造了受约束的宏环,模仿水中的β链结构. 这些稳定的β-链支架为设计针对蛋白质相互作用的药物提供了新的模板.
科学领域:
- 化学生物学 化学生物学
- 结构生物学 结构生物学
- 类化学 类化学
背景情况:
- β-链构成对蛋白质结构和功能至关重要,但其在水溶液中的短中的行为仍然不太清楚.
- β链作为参与蛋白质合成和降解的蛋白质溶解酶的关键识别动机.
研究的目的:
- 设计和合成预先组织成β-链形态的型模拟剂.
- 调查这些新型的溶液中的宏环类同类物质的结构稳定性和形状偏好.
主要方法:
- 合成15-22个成员的三的宏循环类似物.
- 使用可变温度质子核磁共振 (NMR) 光谱学的结构分析.
- 通过二维核磁共振和分子结构计算进行形态分析.
主要成果:
- 宏循环在胺键周围表现出有限的旋转,表明显著的环应变和形状刚性.
- 异常大的氨基酸合常数和温度独立的氨基酸NH化学转移表明各种溶剂中的β-链结构定义得很好.
- 与传统的循环不同,这些宏循环在水中保持了稳定的β-链形态.
结论:
- 受到约束的宏循环可以有效地模仿水溶液中的β链结构.
- 这些预先组织的β-链架构代表了开发β-链介导生物相互作用的抑制剂的有希望的模板.
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