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

• DOI: 10.1038/s41467-024-46721-x
• Publication Date: 2024-03-21T14:03:02Z
• Authors: Darryl M. Wilson; Daniel J. Driedger; Dennis Y. Liu; Sandra Keerthisinghe; Adrian Hermann; Christoph Bieniossek; Roger G. Linington; Robert A. Britton
• Keywords: Natural product; Chemical space

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