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

Grigalunas, M, Burhop, A, Zinken, S, Pahl, A, Gally, J-M, Wild, N, Mantel, Y, Sievers, S, Foley, DJ, Scheel, R, Strohmann, C, Antonchick, AP ORCID: https://orcid.org/0000-0003-0435-9443 and Waldmann, H, 2021. Natural product fragment combination to performance-diverse pseudo-natural products. Nature Communications, 12 (1): 1883.

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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.

Item Type:	Journal article
Publication Title:	Nature Communications
Creators:	Grigalunas, M., Burhop, A., Zinken, S., Pahl, A., Gally, J.-M., Wild, N., Mantel, Y., Sievers, S., Foley, D.J., Scheel, R., Strohmann, C., Antonchick, A.P. and Waldmann, H.
Publisher:	Springer Science and Business Media LLC
Date:	December 2021
Volume:	12
Number:	1
Identifiers:	Number Type 10.1038/s41467-021-22174-4 DOI 1447741 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	01 Jul 2021 09:20
Last Modified:	01 Jul 2021 09:20
URI:	https://irep.ntu.ac.uk/id/eprint/43283

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