混合立体化学宏循环作为螺旋稳定N-Cap
Fabian Hink1, Julen Aduriz-Arrizabalaga2, Xabier Lopez2
1Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark.
Journal of the American Chemical Society
|August 25, 2024
概括
研究人员开发了一种新型的螺旋拉里亚特 (Heliats),通过稳定α-螺旋结构来抑制Mcl-1蛋白. 这些宏环对向蛋白-蛋白相互作用的药物发现具有前景.
科学领域:
- 医学化学
- 结构生物学
- 药物发现
背景情况:
- 涉及阿尔法螺旋的蛋白与蛋白相互作用是药物发现的关键目标.
- 对于开发抑制剂来说,阿尔法螺旋体的大型接口具有挑战性.
- 宏环具有稳定螺旋结构和抑制这些相互作用的潜力.
研究的目的:
- 研究N端到侧链的乙烯环化作为α螺旋结合蛋白Mcl-1的抑制剂.
- 为了选一个万亿级图书馆强大的Mcl-1抑制剂.
- 描述新型螺旋拉里亚特 (Heliat) 抑制剂的结构-活性关系.
主要方法:
- 选一个万亿级的改造的图书馆.
- 使用纳米分子 (nM) 试验确定亲和力.
- 对螺旋稳定性和形状的影响的结构分析.
- 包含最小宏循环动机的修饰的合成.
主要成果:
- 确定了与Mcl-1结合的"螺旋拉里亚特" (螺旋拉里亚特).
- 酸盐有效抑制Mcl-1及其天然配体之间的相互作用.
- 宏环化显著提高了阿尔法螺旋结构的稳定性,亲和力和抑制功效.
- 在N-终端位置的D-立体化学显示出优异的螺旋稳定性.
结论:
- N端到侧链的乙烯环化 (Heliats) 是Mcl-1的强有力的抑制剂.
- 宏循环化是稳定螺旋并改善药物特性的一种可行的策略.
- 开发的混合立体化学宏环N-cap可通过合成获得,并可快速生成螺旋聚焦的库,用于*de novo*抑制剂的发现.
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