Use of Density Functional Calculations To Predict the Regioselectivity of Drugs and Molecules Metabolized by Aldehyde Oxidase
详细信息 查看全文
- 作者：Rhonda A. Torres ; Kenneth R. Korzekwa ; Daniel R. McMasters ; Christine M. Fandozzi ; Jeffrey P. Jones
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：September 20, 2007
- 年：2007
- 卷：50
- 期：19
- 页码：4642 - 4647
- 全文大小：196K
- 年卷期：v.50,no.19(September 20, 2007)
- ISSN：1520-4804
文摘
Aldehyde oxidase is a molybdenum hydroxylase that catalyzes the oxidation of aldehydes and nitrogen-containing heterocycles. The enzyme plays a dual role in the metabolism of physiologically importantendogenous compounds and the biotransformation of xenobiotics. Using density functional theory methods,geometry optimization of tetrahedral intermediates of drugs and druglike compounds was examined to predictthe likely metabolites of aldehyde oxidase. The calculations suggest that the lowest energy tetrahedralintermediate resulting from the initial substrate corresponds to the observed metabolite 90% of the time.Additional calculations were performed on a series of heterocyclic compounds where the products resultingfrom metabolism by xanthine oxidase and aldehyde oxidase differ in many instances. Again, the lowestenergy tetrahedral intermediate corresponded to the observed product of aldehyde oxidase metabolism 90%for the compounds examined, while the observed products of xanthine oxidase were not well predicted.