Identification of isoform/domain-selective fragments from the selection of DNA-encoded dynamic library
Identification of isoform/domain-selective fragments from the selection of DNA-encoded dynamic library
复制标题
从 DNA 编码动态文库的选择中鉴定异构体/结构域选择性片段
DOI：
10.1016/j.bmc.2021.116328
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发表时间：
2021
影响因子：
3.5
通讯作者：
Li Xiaoyu
中科院分区：
文献类型：
--
作者：
Zhou Yu;Shen Wenyin;Peng Jianzhao;Deng Yuqing;Li Xiaoyu
DNA编码的化学文库（DEL）已成为药物筛选中一种强有力的配体筛选技术。最近，我们报道了一种DNA编码的动态库（DEDL）方法，它结合了传统的动态组合库（DCL）和DEL的原理。DEDL在基于片段的配体发现中显示出优异的潜力，具有多种蛋白质靶点。在这里，我们进一步测试了DEDL在鉴定对相同蛋白质家族的不同同种型或结构域具有选择性的低分子量片段中的效用。分别针对沉默调节蛋白-1，2和5（SIRT 1，2，5）以及溴结构域4（BRD 4）的BD 1和BD 2结构域选择10，000个成员的DEDL。尽管具有适度的效力，但鉴定了一系列同种型/结构域选择性片段，并通过片段连接得到相应的抑制剂。
DNA-encoded chemical library (DEL) has emerged to be a powerful ligand screening technology in drug discovery. Recently, we reported a DNA-encoded dynamic library (DEDL) approach that combines the principle of traditional dynamic combinatorial library (DCL) with DEL. DEDL has shown excellent potential in fragment-based ligand discovery with a variety of protein targets. Here, we further tested the utility of DEDL in identifying low molecular weight fragments that are selective for different isoforms or domains of the same protein family. A 10,000-member DEDL was selected against sirtuin-1, 2, and 5 (SIRT1, 2, 5) and the BD1 and BD2 domains of bromodomain 4 (BRD4), respectively. Albeit with modest potency, a series of isoform/domain-selective fragments were identified and the corresponding inhibitors were derived by fragment linking.