AOX 中的结构-代谢关系：来自大数据库中含氮芳香族和酰胺化合物的化学见解。
Structure-metabolism relationships in AOX: Chemical insights from a large database of aza-aromatic and amide compounds.
机构信息
Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy.
Roche Pharma Research and Early Development, Drug Disposition and Safety, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., 4070 Basel, Switzerland.
出版信息
Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3178-E3187. doi: 10.1073/pnas.1618881114. Epub 2017 Apr 3.
Abstract
Aldehyde oxidase (AOX) is a metabolic enzyme catalyzing the oxidation of aldehyde and aza-aromatic compounds and the hydrolysis of amides, moieties frequently shared by the majority of drugs. Despite its key role in human metabolism, to date only fragmentary information about the chemical features responsible for AOX susceptibility are reported and only "very local" structure-metabolism relationships based on a small number of similar compounds have been developed. This study reports a more comprehensive coverage of the chemical space of structures with a high risk of AOX phase I metabolism in humans. More than 270 compounds were studied to identify the site of metabolism and the metabolite(s). Both electronic [supported by density functional theory (DFT) calculations] and exposure effects were considered when rationalizing the structure-metabolism relationship.
摘要
醛氧化酶（AOX）是一种代谢酶，可催化醛和杂环芳香族化合物的氧化以及酰胺的水解，这些部分经常存在于大多数药物中。尽管 AOX 在人类代谢中起着关键作用，但迄今为止，仅报道了与 AOX 易感性相关的化学特征的零碎信息，并且仅基于少数类似化合物开发了“非常局部”的结构-代谢关系。本研究报告了对具有人类 AOX 一期代谢高风险的结构的化学空间的更全面的覆盖。研究了 270 多种化合物以确定代谢部位和代谢产物。在合理化结构-代谢关系时，同时考虑了电子（由密度泛函理论（DFT）计算支持）和暴露效应。
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