Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

Herein, we demonstrate the use of a commercially available enzymatic kit to achieve late-stage hydroxylation of biologically relevant compounds by using the PolyCYPs screening kit. A selection of promising biotransformations were scaled up, products isolated, and structures elucidated. Isolated compounds were screened against a range of pathogens, namely, <i>Schistosoma mansoni</i>, <i>Leishmania donovani</i>, <i>Trypanosoma cruzi</i>, and <i>Trypanosoma brucei</i> to obtain biological data. This approach has allowed data generation more efficiently than the chemical synthesis of the same molecules. Importantly, it has been demonstrated that production of hits of interest can also be scaled up to enable further study. We also demonstrate the biosynthetic synthesis of a lead compound in fewer steps than using standard synthetic chemistry, offering faster access to compounds for screening or further transformation. This approach has the potential to save time and resources in a drug discovery program, by reducing the necessity to synthesize late-stage intermediates and develop new chemistry.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-10-12
DOI
https://doi.org/10.1021/acs.jmedchem.5c01467
Primary Topic
Pharmacogenetics and Drug Metabolism
Type
article
Field-Weighted Citation Impact
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article

Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

Vincent Kwok‐Man Poon, Gary J. Tarver, Sandra Carvalho, Ian H. Gilbert et al.
Journal of Medicinal Chemistry
Pharmacogenetics and Drug Metabolism
article

Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

Vincent Kwok‐Man Poon, Gary J. Tarver, Sandra Carvalho, Ian H. Gilbert, Susan Wyllie, Stephen K. Wrigley, Karl F. Hoffmann, Lisbet Kværnø, John Boyle, Ravi Manohar, Christopher L. Drake, James W. B. Fyfe, Jonathan Steele, Tetsuo Kokubun, Josephine Forde-Thomas, Olga Semenova, Kennedy R. Lees, Christopher Bailey, Stephen Patterson, Emily Hopkins
article en

Abstract

Herein, we demonstrate the use of a commercially available enzymatic kit to achieve late-stage hydroxylation of biologically relevant compounds by using the PolyCYPs screening kit. A selection of promising biotransformations were scaled up, products isolated, and structures elucidated. Isolated compounds were screened against a range of pathogens, namely, <i>Schistosoma mansoni</i>, <i>Leishmania donovani</i>, <i>Trypanosoma cruzi</i>, and <i>Trypanosoma brucei</i> to obtain biological data. This approach has allowed data generation more efficiently than the chemical synthesis of the same molecules. Importantly, it has been demonstrated that production of hits of interest can also be scaled up to enable further study. We also demonstrate the biosynthetic synthesis of a lead compound in fewer steps than using standard synthetic chemistry, offering faster access to compounds for screening or further transformation. This approach has the potential to save time and resources in a drug discovery program, by reducing the necessity to synthesize late-stage intermediates and develop new chemistry.

Journal of Medicinal ChemistryVol. 68(20)
Aberystwyth University (GB), University of Dundee (GB), Discovery Centre (CA), Hypha Discovery (United Kingdom) (GB), Wellcome Centre for Anti-Infectives Research (GB)
Openalex Percentile: Top 63%
Pharmacogenetics and Drug Metabolism
DOIOpen Access PDFOpenAlex
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