吞吐量
组合化学
DNA测序
高通量筛选
鉴定(生物学)
作者
Wenji Su,Rui Ge,Duanchen Ding,Wenhua Chen,Wenqing Wang,Hao Yan,Weikun Wang,Youlang Yuan,Huan Liu,Meng Zhang,Jiyuan Zhang,Shu Qisheng,Alexander L. Satz,Kuai Letian
标识
DOI:10.1021/acs.bioconjchem.1c00170
摘要
DNA encoded library (DEL) technology allows for rapid identification of novel small-molecule ligands and thus enables early-stage drug discovery. DEL technology is well-established, numerous cases of discovered hit molecules have been published, and the technology is widely employed throughout the pharmaceutical industry. Nonetheless, DEL selection results can be difficult to interpret, as library member enrichment may derive from not only desired products, but also DNA-conjugated byproducts and starting materials. Note that DELs are generally produced using split-and-pool combinatorial chemistry, and DNA-conjugated byproducts and starting materials cannot be removed from the library mixture. Herein, we describe a method for high-throughput parallel resynthesis of DNA-conjugated molecules such that byproducts, starting materials, and desired products are produced in a single pot, using the same chemical reactions and reagents as during library production. The low-complexity mixtures of DNA-conjugate are then assessed for protein binding by affinity selection mass spectrometry and the molecular weights of the binding ligands ascertained. This workflow is demonstrated to be a practical tool to triage and validate potential hits from DEL selection data.
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