结构多样化的宏观循环的大型库适合膜透
Alexander L Nielsen1, Zsolt Bognar1, Ganesh K Mothukuri1
1Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
Angewandte Chemie (International ed. in English)
|April 11, 2024
概括
研究人员为药物发现开发了各种宏环,增强了骨复杂性和膜透性. 这种方法扩大了针对各种治疗点的药物开发可能性.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
- 药物发现 药物发现 药物发现
背景情况:
- 由于强大的结合和细胞透性,宏观循环是有希望的药物候选者.
- 目前的方法经常使用不变的含醇氨基酸,限制多样性和增加大小.
研究的目的:
- 开发新的,结构多样化的宏环,使用可变的含元素.
- 创建一个大型的宏观循环的组合图书馆,增强骨的复杂性.
- 鉴定具有良好的膜透性的强效血栓和血卡利克林抑制剂.
主要方法:
- 合成了各种含有硫醇的构建块.
- 构建了2,688个成员的性宏循环的组合图书馆.
- 选了酶抑制剂的图书馆,并评估了膜透性.
- 利用X射线晶体学分析宏循环-目标相互作用.
主要成果:
- 成功合成了一个结构复杂的宏观循环库.
- 发现了强效的血栓激素和血抑制剂kallikrein.
- 鉴定出具有良好的膜透性的化合物.
- X射线分析证实了醇元素大小和形状对结合的重要性.
结论:
- 新战略显著提高了宏环库的结构多样性.
- 这种方法允许对以前不变的区域进行组合修改.
- 开发的宏循环显示出创造膜透性疗法的潜力.
- 这种方法可以在药物开发中广泛应用于各种目标.
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