Human metabolites of bosentan produced by enzymes in Hypha's Polycyps ™ cytochrome P450 kit

Steele, Jonathan; Riso, Antonio De; Williams, Headley; Phipps, Richard P.; Bardoni, Silvia; rake, Chris; Wrigley, Stephen K.; Shanu-Wilson, Julia; Scheffler, Frank; Schulz, Sebastian; Ward, John W.

doi:10.1016/j.dmpk.2017.11.121

Cited by 3 publications

(1 citation statement)

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“…52 In many cases microbial oxygenases have high turnover and good operational stability 53 and bacterial CYPs usually have much higher specific activities 50 and thus are more suitable biocatalysts for obtaining scalable quantities of derivatives. Recombinant microbial-derived CYP kits are convenient for determining susceptibility of lead compounds to biotransformation by oxidation, such as PolyCYPs enzymes, composed of a diverse set of recombinant CYPs cloned from actinomycete strains with known oxidizing ability, and expressed in E. coli together with the appropriate redox partners, 54 and MicroCyps, derived from a series of mutants of the fatty acid hydroxylase CYP from Bacillus megaterium (BM3). Both systems enable scalable synthesis of CYP-derived human metabolites for definitive metabolite identification and pharmacological testing.…”

Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

Biotransformation: Impact and Application of Metabolism in Drug Discovery

Shanu-Wilson

Evans

Wrigley

et al. 2020

ACS Med. Chem. Lett.

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Biotransformation has a huge impact on the efficacy and safety of drugs. Ultimately the effects of metabolism can be the lynchpin in the discovery and development cycle of a new drug. This article discusses the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design from the combined perspectives of a CRO specializing in a range of biotransformation techniques and pharma biotransformation scientists. We include a commentary on how biology-driven approaches can complement medicinal chemistry strategies in drug optimization and the in vitro and surrogate systems available to explore and exploit biotransformation.

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Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

Biotransformation: Impact and Application of Metabolism in Drug Discovery

Shanu-Wilson

Evans

Wrigley

et al. 2020

ACS Med. Chem. Lett.

Self Cite

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Methods for metabolite generation and characterization by NMR

Evans

Phipps

Shanu-Wilson

et al. 2020

Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters

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Microbial biotransformation – an important tool for the study of drug metabolism

et al. 2018

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Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies. Examples of the microbial synthesis of several difficult-to-synthesize hydroxylated metabolites and three difficult-to-synthesize glucuronidated metabolites are described, and the use of microbial biotransformation in drug discovery and development is discussed.

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Human metabolites of bosentan produced by enzymes in Hypha's Polycyps ™ cytochrome P450 kit

Cited by 3 publications

References 0 publications

Biotransformation: Impact and Application of Metabolism in Drug Discovery

Biotransformation: Impact and Application of Metabolism in Drug Discovery

Methods for metabolite generation and characterization by NMR

Microbial biotransformation – an important tool for the study of drug metabolism

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