Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase
Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase
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DOI：
10.1021/jm0703690
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发表时间：
2007-09-20
影响因子：
7.3
通讯作者：
Jones, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Torres, Rhonda A.;Korzekwa, Kenneth R.;Jones, Jeffrey P.
醛氧化酶是一种钼羟化酶，催化醛和含氮杂环的氧化。该酶在生理上重要的内源性化合物的代谢和外源物的生物转化中起双重作用。采用密度泛函理论方法，对药物和类药物化合物的四面体中间体进行几何优化，以预测醛氧化酶可能的代谢产物。计算表明，由初始底物产生的最低能量的四面体中间体在90%的情况下对应于观察到的代谢物>=。对一系列杂环化合物进行了额外的计算，其中黄嘌呤氧化酶和醛氧化酶代谢产生的产物在许多情况下不同。同样，最低能量的四面体中间体对应于所检测化合物的醛氧化酶代谢的观察产物>= 90%，而黄嘌呤氧化酶的观察产物不能很好地预测。
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 important endogenous compounds and the biotransformation of xenobiotics. Using density functional theory methods, geometry optimization of tetrahedral intermediates of drugs and druglike compounds was examined to predict the likely metabolites of aldehyde oxidase. The calculations suggest that the lowest energy tetrahedral intermediate 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 resulting from metabolism by xanthine oxidase and aldehyde oxidase differ in many instances. Again, the lowest energy 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.