title: Flavin monooxygenase metabolism: why medicinal chemists should matter.
abstract: FMO enzymes (FMOs) play a key role in the processes of detoxification and/or bioactivation of specific pharmaceuticals and xenobiotics bearing nucleophilic centers. The N-oxide and S-oxide metabolites produced by FMOs are often active metabolites. The FMOs are more active than cytochromes in the brain and work in tandem with CYP3A4 in the liver. FMOs might reduce the risk of phospholipidosis of CAD-like drugs, although some FMOs metabolites seem to be neurotoxic and hepatotoxic. However, in silico methods for FMO metabolism prediction are not yet available. This paper reports, for the first time, a substrate-specificity and catalytic-activity model for FMO3, the most relevant isoform of the FMOs in humans. The application of this model to a series of compounds with unknown FMO metabolism is also reported. The model has also been very useful to design compounds with optimal clearance and in finding erroneous literature data, particularly cases in which substances have been reported to be FMO3 substrates when, in reality, the experimentally validated in silico model correctly predicts that they are not.
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , Via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Aurora
authors.initials: A
authors.lastname: Valeri
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.forename: Roberto Maria
authors.initials: RM
authors.lastname: Pellegrino
authors.forename: Federica
authors.initials: F
authors.lastname: Buonerba
authors.forename: Massimo
authors.initials: M
authors.lastname: Baroni
mesh_terms: D055162:Biocatalysis; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010105:Oxygenases / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results; D013379:Substrate Specificity
chemical_list: D011994:Recombinant Proteins; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)