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Natural product fragment combination to performance-diverse pseudo-natural products

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment...

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Autores principales: Grigalunas, Michael, Burhop, Annina, Zinken, Sarah, Pahl, Axel, Gally, José-Manuel, Wild, Niklas, Mantel, Yannik, Sievers, Sonja, Foley, Daniel J., Scheel, Rebecca, Strohmann, Carsten, Antonchick, Andrey P., Waldmann, Herbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994817/
https://www.ncbi.nlm.nih.gov/pubmed/33767198
http://dx.doi.org/10.1038/s41467-021-22174-4
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author Grigalunas, Michael
Burhop, Annina
Zinken, Sarah
Pahl, Axel
Gally, José-Manuel
Wild, Niklas
Mantel, Yannik
Sievers, Sonja
Foley, Daniel J.
Scheel, Rebecca
Strohmann, Carsten
Antonchick, Andrey P.
Waldmann, Herbert
author_facet Grigalunas, Michael
Burhop, Annina
Zinken, Sarah
Pahl, Axel
Gally, José-Manuel
Wild, Niklas
Mantel, Yannik
Sievers, Sonja
Foley, Daniel J.
Scheel, Rebecca
Strohmann, Carsten
Antonchick, Andrey P.
Waldmann, Herbert
author_sort Grigalunas, Michael
collection PubMed
description Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
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spelling pubmed-79948172021-04-16 Natural product fragment combination to performance-diverse pseudo-natural products Grigalunas, Michael Burhop, Annina Zinken, Sarah Pahl, Axel Gally, José-Manuel Wild, Niklas Mantel, Yannik Sievers, Sonja Foley, Daniel J. Scheel, Rebecca Strohmann, Carsten Antonchick, Andrey P. Waldmann, Herbert Nat Commun Article Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space. Nature Publishing Group UK 2021-03-25 /pmc/articles/PMC7994817/ /pubmed/33767198 http://dx.doi.org/10.1038/s41467-021-22174-4 Text en © The Author(s) 2021 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/.
spellingShingle Article
Grigalunas, Michael
Burhop, Annina
Zinken, Sarah
Pahl, Axel
Gally, José-Manuel
Wild, Niklas
Mantel, Yannik
Sievers, Sonja
Foley, Daniel J.
Scheel, Rebecca
Strohmann, Carsten
Antonchick, Andrey P.
Waldmann, Herbert
Natural product fragment combination to performance-diverse pseudo-natural products
title Natural product fragment combination to performance-diverse pseudo-natural products
title_full Natural product fragment combination to performance-diverse pseudo-natural products
title_fullStr Natural product fragment combination to performance-diverse pseudo-natural products
title_full_unstemmed Natural product fragment combination to performance-diverse pseudo-natural products
title_short Natural product fragment combination to performance-diverse pseudo-natural products
title_sort natural product fragment combination to performance-diverse pseudo-natural products
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994817/
https://www.ncbi.nlm.nih.gov/pubmed/33767198
http://dx.doi.org/10.1038/s41467-021-22174-4
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