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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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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
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author Cui, Meiying
Nguyen, Dzung
Gaillez, Michelle Patino
Heiden, Stephan
Lin, Weilin
Thompson, Michael
Reddavide, Francesco V.
Chen, Qinchang
Zhang, Yixin
author_facet Cui, Meiying
Nguyen, Dzung
Gaillez, Michelle Patino
Heiden, Stephan
Lin, Weilin
Thompson, Michael
Reddavide, Francesco V.
Chen, Qinchang
Zhang, Yixin
author_sort Cui, Meiying
collection PubMed
description 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.
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spelling pubmed-100237872023-03-19 Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers Cui, Meiying Nguyen, Dzung Gaillez, Michelle Patino Heiden, Stephan Lin, Weilin Thompson, Michael Reddavide, Francesco V. Chen, Qinchang Zhang, Yixin Nat Commun Article 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. Nature Publishing Group UK 2023-03-17 /pmc/articles/PMC10023787/ /pubmed/36932079 http://dx.doi.org/10.1038/s41467-023-37071-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cui, Meiying
Nguyen, Dzung
Gaillez, Michelle Patino
Heiden, Stephan
Lin, Weilin
Thompson, Michael
Reddavide, Francesco V.
Chen, Qinchang
Zhang, Yixin
Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title_full Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title_fullStr Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title_full_unstemmed Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title_short Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
title_sort trio-pharmacophore dna-encoded chemical library for simultaneous selection of fragments and linkers
topic Article
url 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
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