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.

DNA 编码的化学库 (DEL) 已成为药物发现中一种强大的配体筛选技术。最近，我们报道了一种 DNA 编码的动态库 (DEDL) 方法，该方法将传统动态组合库 (DCL) 的原理与 DEL 相结合。DEDL 在多种蛋白质靶标的基于片段的配体发现中显示出巨大的潜力。在这里，我们进一步测试了 DEDL 在识别对同一蛋白质家族的不同亚型或结构域具有选择性的低分子量片段方面的效用。分别针对 sirtuin-1、2 和 5（SIRT1、2、5）以及溴结构域 4（BRD4）的 BD1 和 BD2 域选择了 10,000 名成员的 DEDL。尽管效力适中，但已鉴定出一系列同工型/结构域选择性片段，并通过片段连接衍生出相应的抑制剂。