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

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 m...

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Detalles Bibliográficos
Autores principales: Cui, Meiying, Nguyen, Dzung, Gaillez, Michelle Patino, Heiden, Stephan, Lin, Weilin, Thompson, Michael, Reddavide, Francesco V., Chen, Qinchang, Zhang, Yixin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023787/
https://www.ncbi.nlm.nih.gov/pubmed/36932079
http://dx.doi.org/10.1038/s41467-023-37071-1
Descripción
Sumario: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.