Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library.
Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library.
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DOI：
10.1177/2472555218808454
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Evindar G
中科院分区：
文献类型：
--
作者：
Zhu Z;Grady LC;Ding Y;Lind KE;Davie CP;Phelps CB;Evindar G
DNA编码文库（DELs）已被广泛应用于鉴定用于靶标验证和先导物发现的化学探针。迄今为止，DEL平台的主要应用是使用多轮亲和选择鉴定可逆配体。不可逆（共价）抑制为药物发现研究提供了独特的作用机制。在这项研究中，我们报告了一个开发中的方法，确定不可逆的（共价）配体从DEL。通过使用3C蛋白酶（3CP）和DNA上不可逆的工具化合物（ruptavir衍生物）以与该文库的单个成员相同的浓度掺入文库中来验证新方法。在针对3CP的亲和选择后，与文库成员相比，不可逆工具化合物被特异性富集。此外，我们比较了两种固定化方法，并得出结论，与适当的亲和树脂填充的微型柱得到更高的工具化合物回收率比磁珠。
DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research. In this study, we report a developing method of identifying irreversible (covalent) ligands from DELs. The new method was validated by using 3C protease (3CP) and on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into a library at the same concentration as individual members of that library. After affinity selections against 3CP, the irreversible tool compounds were specifically enriched compared with the library members. In addition, we compared two immobilization methods and concluded that microscale columns packed with the appropriate affinity resin gave higher tool compound recovery than magnetic beads.
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