Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should Matter

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.