Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should Matter
Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should Matter
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DOI：
10.1021/jm5007098
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发表时间：
2014-07-24
影响因子：
7.3
通讯作者：
Baroni, Massimo
中科院分区：
文献类型：
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作者：
Cruciani, Gabriele;Valeri, Aurora;Baroni, Massimo
FMO酶（FMO）在具有亲核中心的特定药物和异生物质的解毒和/或生物活化过程中起关键作用。由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在大脑中比细胞色素更活跃，并与肝脏中的CYP 3A 4协同工作。FMOs可能降低CAD样药物的磷脂质沉积风险，尽管一些FMOs代谢产物似乎具有神经毒性和肝毒性。然而，目前还没有用于FMO代谢预测的计算机模拟方法。本文首次报道了FMO 3的底物特异性和催化活性模型，FMO 3是人体中FMOs最相关的亚型。还报道了该模型对一系列未知FMO代谢的化合物的应用。该模型也非常有助于设计具有最佳清除率的化合物，并发现错误的文献数据，特别是在物质被报告为FMO 3底物的情况下，实际上，实验验证的计算机模型正确预测它们不是。
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.