为正确的位置找到合适的候选人:用于优化核酸结合物的快速NMR辅助组合方法
Ester Jiménez-Moreno1, Laura Montalvillo-Jiménez1, Andrés G Santana1
1Instituto de Química Orgánica (IQOG-CSIC) , Juan de la Cierva 3, 28006 Madrid, Spain.
Journal of the American Chemical Society
|April 29, 2016
概括
这项研究引入了一种基于片段的新方法,以优化结合DNA/RNA的候选药物. 它使用NMR快速测试许多化合物, 加快药物发现.
科学领域:
- 医学化学
- 结构生物学
- 药物发现
背景情况:
- 在药物发现中,将化合物优化为选择性药物结合剂是一个昂贵而漫长的过程.
- 多价聚胺支架对DNA/RNA连接体的开发具有前景.
- 基于片段的药物设计需要有效的图书馆合成和选方法.
研究的目的:
- 提出一种基于片段的新组合策略,以优化多价值聚胺支架作为DNA/RNA联体.
- 展示一个快速生成和测试区域图书馆的方法.
- 评估NMR光谱在复杂化合物混合物的高通量选中的实用性.
主要方法:
- 使用基于碎片的组合策略来优化脚手架.
- 使用微透析测定与同位素标记和NMR实验进行化合物评估.
- 合成了100种新的卡纳米辛-B衍生物,并对选择性结合进行了选.
主要成果:
- 开发的协议可以快速访问不同区域的图书馆.
- 核磁共振方法在检测和量化类似化合物的复杂混合物方面是有效的.
- 对合成的衍生物进行了选择性结合与核糖体解码A位序的评估.
结论:
- 这种基于NMR的方法为优化提供了有价值的高吞吐量替代方案.
- 该研究提供了对选择性A站点识别的结构要求的见解.
- 这种策略加快了强效和选择性的DNA/RNA配体的发展.
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