The Cytochrome P450 superfamily is renowned for its ability to catalyze the oxyfunctionalization of diverse organic substrates, playing a pivotal role in both biocatalysis and drug metabolism. Our work led to the development of light-driven P450 biocatalysts, utilizing an inorganic Ru(II)-polypyridyl photosensitizer paired with an appropriate sacrificial electron source to facilitate oxygen atom insertion into unactivated C-H bonds upon visible light excitation. By strategically positioning the photosensitizer near the heme active site, we achieved efficient electron transfer, resulting in hybrid enzymes with remarkable photocatalytic activity across a spectrum of substrates. We will provide an overview of recent advancements, emphasizing the methodology and burgeoning developments in chemoenzymatic reactions.
In recent years, our focus has shifted towards the critical role that metabolism and metabolite identification play in the drug discovery and development process within a Big Pharma setting. Of particular interest are the identification of reactive metabolites and their implications in drug-induced liver injury (DILI). In vitro trapping assays using glutathione or cyanide are utilized to capture soft or hard electrophiles, respectively and assess the potential for reactive metabolites formation. Meanwhile, their translatability to humans remains a challenge. Our latest efforts have centered around Cytochrome P450 mediated formation of iminium ions within cyclic amines, which are increasingly prevalent in approved drug structures. We will present an overview of current assays for identifying reactive metabolites and structural alerts and discuss ongoing strategies to identify/mitigate potential liabilities in drug molecules.