Accessing active fragments for drug discovery utilising nitroreductase biocatalysis.

Holder, Lauren; Yuce, Eda; Oriomah, Gabriel; Jenkins, Aimee-Page; Reynisson, Jóhannes; Winter, Anja; Cosgrove, Sebastian

Abstract

Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR-55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials. After screening on analytical scale, we show that sixteen substrates could be scaled to 1 mmol scale, with several poly-functional anilines afforded with ease under the standard conditions. The aniline products were also screened for activity against several cell lines of interest, with modest activity observed for one compound. This study demonstrates the potential for nitroreductase biocatalysis to provide access to functional fragments under benign conditions. [Abstract copyright: © 2024 Wiley‐VCH GmbH.]

Citation

Holder, L., Yuce, E., Oriomah, G., Jenkins, A.-P., Reynisson, J., Winter, A., & Cosgrove, S. (in press). Accessing active fragments for drug discovery utilising nitroreductase biocatalysis. ChemBioChem, 25(18), Article e202400428. https://doi.org/10.1002/cbic.202400428

• Journal Article Type: Article
• Acceptance Date: Jun 27, 2024
• Online Publication Date: Jun 28, 2024
• Deposit Date: Jul 15, 2024
• Journal: Chembiochem : a European journal of chemical biology
• Print ISSN: 1439-4227
• Electronic ISSN: 1439-7633
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 18
• Article Number: e202400428
• DOI: https://doi.org/10.1002/cbic.202400428
• Keywords: Nitroreductase, aniline fragments, Biocatalysis, FBDD
• Public URL: https://keele-repository.worktribe.com/output/875234