Understanding P450‐mediated Bio‐transformations into Epoxide and Phenolic Metabolites. Issue 46 (29th September 2015)

• Record Type: Journal Article
• Authors: Tomberg, Anna; Pottel, Joshua; Liu, Zhaomin; Labute, Paul; Moitessier, Nicolas
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 46(2015)
• Page Start: 13743
• Page End: 13747
• Publication Date: 2015-09-29
• Subjects: computational chemistry -- cytochromes -- frontier‐orbital model -- metabolism -- toxicology; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201506131
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Adverse drug reactions are commonly the result of cytochrome P450 enzymes (CYPs) converting the drugs into reactive metabolites. Thus, information about the CYP bioactivation of drugs would not only provide insight into metabolic stability, but also into the potential toxicity. For example, oxidation of phenyl rings may lead to either toxic epoxides or safer phenols. Herein, we demonstrate that the potential to form reactive metabolites is encoded primarily in the properties of the molecule to be oxidized. While the enzyme positions the molecule inside the binding pocket (selects the site of metabolism), the subsequent reaction is only dependent on the substrate itself. To test this hypothesis, we used this observation as a predictor of drug inherent toxicity. This approach was used to successfully identify the formation of reactive metabolites in over 100 drug molecules. These results provide a new perspective on the impact of functional groups on aromatic oxidation of drugs and their effects on toxicity. Abstract : The prediction of the metabolism of a compound will enable to speed up the drug discovery process by discarding potentially toxic drug candidates at an early stage. This study focuses on the oxidation of small molecules by cytochrome P450 enzymes, which metabolize most drugs. The metabolites formed by this bio‐transformation can be identified directly from the molecular orbitals of a compound.