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

Darryl M. Wilson, Daniel J. Driedger, Dennis Y. Liu, Sandra Keerthisinghe, Adrian Hermann, Christoph Bieniossek, Roger G. Linington () and Robert A. Britton ()
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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
Robert A. Britton: Simon Fraser University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46721-x

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