Abstract
Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small-molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel ‘pseudo-natural product’ classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we identify design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small-molecule discovery.
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The material and data reported in this study are available from the corresponding author upon request.
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Acknowledgements
This research was supported by the Max-Planck-Gesellschaft. G.K. is grateful to the Alexander von Humboldt Foundation for a fellowship. D.J.F. is grateful to the European Commission for a Marie Skłodowska-Curie Fellowship (grant 794259). L.L. is grateful to the Novo Nordisk Foundation and DTU for funding.
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G.K. performed the cheminformatic analyses. All authors contributed to discussions about the connectivity types and design principles for pseudo-natural product classes. G.K., D.J.F, L.L. and H.W. wrote the paper.
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Karageorgis, G., Foley, D.J., Laraia, L. et al. Principle and design of pseudo-natural products. Nat. Chem. 12, 227–235 (2020). https://doi.org/10.1038/s41557-019-0411-x
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DOI: https://doi.org/10.1038/s41557-019-0411-x
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