Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia , Via Elce di Sotto 8, 06123 Perugia, Italy.
J Med Chem. 2014 Jul 24;57(14):6183-96. doi: 10.1021/jm5007098. Epub 2014 Jul 15.
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.
黄素单加氧酶（FMO）在具有亲核中心的特定药物和外源性化合物的解毒和/或生物活化过程中发挥关键作用。FMO 产生的 N-氧化物和 S-氧化物代谢物通常是活性代谢物。FMO 在大脑中的活性高于细胞色素，并且与肝脏中的 CYP3A4 协同作用。FMO 可能降低 CAD 样药物发生磷脂沉积的风险，尽管一些 FMO 代谢物似乎具有神经毒性和肝毒性。然而，目前还没有用于 FMO 代谢预测的计算方法。本文首次报道了人 FMO 中最相关的同工酶 FMO3 的底物特异性和催化活性模型。还报告了该模型在一系列未知 FMO 代谢化合物中的应用。该模型对于设计具有最佳清除率的化合物和发现错误的文献数据也非常有用，特别是当物质被报道为 FMO3 底物时，实际上，经过实验验证的计算模型正确预测它们不是。
