Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers

作者：Meiying Cui, D. Nguyen, Michelle Patino Gaillez, Stephan Heiden, Weilin Lin, Michael C. Thompson, Francesco V. Reddavide, Qinchang Chen, Yixin Zhang · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-37071-1 · 被引用次数：19 · 研究领域：Chemical Synthesis and Analysis、Peptidase Inhibition and Analysis、Click Chemistry and Applications

The split-and-pool method has been widely used to synthesize chemical libraries of a large size for early drug discovery, albeit without the possibility of meaningful quality control. In contrast, a self-assembled DNA-encoded chemical library (DEL) allows us to construct an m x n-member library by mixing an m-member and an n-member pre-purified sub-library. Herein, we report a trio-pharmacophore DEL (T-DEL) of m x l x n members through assembling three pre-purified and validated sub-libraries. The middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms and designed as a linkage connecting the fragments displayed on the flanking two sub-libraries. Despite assembling three fragments, the resulting compounds do not exceed the up-to-date standard of molecular weight regarding drug-likeness. We demonstrate the utility of T-DEL in linker optimization for known binding fragments against trypsin and carbonic anhydrase II and by de novo selections against matrix metalloprotease-2 and -9.