A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes
A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes
复制标题
DOI：
10.1021/jacs.8b08039
复制
发表时间：
2019-04-03
影响因子：
15
通讯作者：
Franzini, Raphael M.
中科院分区：
文献类型：
--
作者：
Yuen, Lik Hang;Dana, Srikanta;Franzini, Raphael M.
DNA编码的化学库越来越多地用于药物研究，因为它们能够快速发现合成蛋白质配体。在这里，我们探讨了目标类集中的DNA编码的化学文库是否可以是具有成本效益的工具，以实现一系列蛋白质的强大筛选生产力。该研究表明，为NAD（+）结合口袋（NADEL）设计的DNA编码文库有效地采样了具有ADP-核糖基转移酶活性的酶的化学结合剂空间。提取的信息指导了包括PARP 15和SIRT 6在内的几种酶的抑制剂的合成。NADEL筛选不同蛋白质的指纹图谱的高度不相似性转化为抑制剂，显示出对其靶标的选择性。发现的模式的富集结构的8个测试的蛋白质中的6个是显着的58 302 DNA标记的结构的库，并说明了前景集中的DNA编码的库作为经济的替代大型库平台。
DNA-encoded chemical libraries are increasingly used in pharmaceutical research because they enable the rapid discovery of synthetic protein ligands. Here we explored whether target-class focused DNA-encoded chemical libraries can be cost-effective tools to achieve robust screening productivity for a series of proteins. The study revealed that a DNA-encoded library designed for NAD(+)-binding pockets (NADEL) effectively sampled the chemical binder space of enzymes with ADP-ribosyltransferase activity. The extracted information directed the synthesis of inhibitors for several enzymes including PARP15 and SIRT6. The high dissimilarity of NADEL screening fingerprints for different proteins translated into inhibitors that showed selectivity for their target. The discovery of patterns of enriched structures for six out of eight tested proteins is remarkable for a library of 58 302 DNA-tagged structures and illustrates the prospect of focused DNA-encoded libraries as economic alternatives to large library platforms.