S139: Codex™ MicroCyp plate for drug metabolite production and lead diversification

Conventional methods for P450 drug metabolite identification and production make use of a variety of commercially available biocatalysts, including microbial libraries, human and animal microsomes, and recombinant P450s.  Many challenges to using P450s for milligram scale drug metabolite production (poor stability, troublesome reconstitution, high cost) have been overcome with Codexis’ Human Cytochrome Biocatalysts.  However, because larger amounts of drug metabolites are needed for toxicology and bioactivity tests, even more efficient P450 biocatalysts are needed.  The Codex™ MicroCyp Plate contains 90 engineered P450 variants of the CYP102A1 enzyme from Bacillus megaterium, evolved for activity toward drug compounds.  The enhanced activity and stability of these bacterial P450 variants along with lower biocatalyst costs allows for cost-effective metabolite production at the 100 mg to gram scale. This high productivity combined with the broad metabolism spectrum, producing human and non-human metabolites, makes the MicroCyps a viable biocatalyst system for lead compound diversification.  Production of metabolites from several human P450 drug substrates from screening to scale-up are compared to reactions using Codexis’ Human Cytochrome Biocatalysts.  In addition, case studies of metabolite production from novel drug candidates using the MicroCyps are presented.