Cytochrome P450 oxidases (CYPs) are heme-containing enzymes responsible for clearing xenobiotics, including drug molecules, from the human body via oxidative metabolism. Understanding and predicting CYP behavior is thus critical for evaluating drug efficacy, clearance, toxicity, and drug-drug interactions. Although dozens of crystal structures of the five predominant CYP isoforms have been solved, most of the modeling tools that predict drug-CYP interactions completely neglect this structural information. In this work, both 2D- and 3D-methods are used to predict the isoform selectivity, small molecule reactivity, and regioselectivity of CYPs. The 2D-based methods are parsimonious yet accurate, and can be used to quickly evaluate selectivity and reactivity. The 3D-method uses a pharmacophoric approach to provide a rapid and flexible way to predict CYP isoform selectivity and regioselectivity. Directly incorporating CYP structural information into the models confers unique advantages over 2D-based approaches, such as the ability to distinguish reactivity differences among stereoisomers. Finally, predicted results can be readily visualized in a CYP pocket, and thus potential CYP liabilities are not merely flagged in a binary fashion, but can also be designed against in a structure-based design context – a clear improvement over the pass/fail filtering standards prevalent in CYP modeling efforts to date.

Structure-based predictions of CYP selectivity, reactivity, and regioselectivity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.