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

Michael Grigalunas, Annina Burhop, Sarah Zinken, Axel Pahl, José-Manuel Gally, Niklas Wild, Yannik Mantel, Sonja Sievers, Daniel J. Foley, Rebecca Scheel, Carsten Strohmann, Andrey P. Antonchick and Herbert Waldmann ()
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Michael Grigalunas: Max Planck Institute of Molecular Physiology
Annina Burhop: Max Planck Institute of Molecular Physiology
Sarah Zinken: Max Planck Institute of Molecular Physiology
Axel Pahl: Max Planck Institute of Molecular Physiology
José-Manuel Gally: Max Planck Institute of Molecular Physiology
Niklas Wild: Max Planck Institute of Molecular Physiology
Yannik Mantel: Max Planck Institute of Molecular Physiology
Sonja Sievers: Max Planck Institute of Molecular Physiology
Daniel J. Foley: Max Planck Institute of Molecular Physiology
Rebecca Scheel: Technical University Dortmund, Faculty of Chemistry and Inorganic Chemistry
Carsten Strohmann: Technical University Dortmund, Faculty of Chemistry and Inorganic Chemistry
Andrey P. Antonchick: Max Planck Institute of Molecular Physiology
Herbert Waldmann: Max Planck Institute of Molecular Physiology

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22174-4

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