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Targeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides

Author

Listed:
  • Darryl M. Wilson

    (Simon Fraser University)

  • Daniel J. Driedger

    (Simon Fraser University)

  • Dennis Y. Liu

    (Simon Fraser University)

  • Sandra Keerthisinghe

    (Simon Fraser University)

  • Adrian Hermann

    (F. Hoffmann-La Roche Ltd)

  • Christoph Bieniossek

    (F. Hoffmann-La Roche Ltd)

  • Roger G. Linington

    (Simon Fraser University
    Simon Fraser University)

  • Robert A. Britton

    (Simon Fraser University)

Abstract

Polyketide or polyketide-like macrolides (pMLs) continue to serve as a source of inspiration for drug discovery. However, their inherent structural and stereochemical complexity challenges efforts to explore related regions of chemical space more broadly. Here, we report a strategy termed the Targeted Sampling of Natural Product space (TSNaP) that is designed to identify and assess regions of chemical space bounded by this important class of molecules. Using TSNaP, a family of tetrahydrofuran-containing pMLs are computationally assembled from pML inspired building blocks to provide a large collection of natural product-like virtual pMLs. By scoring functional group and volumetric overlap against their natural counterparts, a collection of compounds are prioritized for targeted synthesis. Using a modular and stereoselective synthetic approach, a library of polyketide-like macrolides are prepared to sample these unpopulated regions of pML chemical space. Validation of this TSNaP approach by screening this library against a panel of whole-cell biological assays, reveals hit rates exceeding those typically encountered in small molecule libraries. This study suggests that the TSNaP approach may be more broadly useful for the design of improved chemical libraries for drug discovery.

Suggested Citation

  • Darryl M. Wilson & Daniel J. Driedger & Dennis Y. Liu & Sandra Keerthisinghe & Adrian Hermann & Christoph Bieniossek & Roger G. Linington & Robert A. Britton, 2024. "Targeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46721-x
    DOI: 10.1038/s41467-024-46721-x
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    References listed on IDEAS

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    1. Ian B. Seiple & Ziyang Zhang & Pavol Jakubec & Audrey Langlois-Mercier & Peter M. Wright & Daniel T. Hog & Kazuo Yabu & Senkara Rao Allu & Takehiro Fukuzaki & Peter N. Carlsen & Yoshiaki Kitamura & Xi, 2016. "A platform for the discovery of new macrolide antibiotics," Nature, Nature, vol. 533(7603), pages 338-345, May.
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