Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase

J Med Chem. 2007 Sep 20;50(19):4642-7. doi: 10.1021/jm0703690. Epub 2007 Aug 25.


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 >or=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 >or=90% for the compounds examined, while the observed products of xanthine oxidase were not well predicted.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Oxidase / chemistry*
  • Aldehyde Oxidase / metabolism
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / metabolism
  • Models, Molecular*
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism
  • Quantitative Structure-Activity Relationship*
  • Stereoisomerism
  • Thermodynamics
  • Xanthine Oxidase / chemistry
  • Xanthine Oxidase / metabolism


  • Heterocyclic Compounds
  • Pharmaceutical Preparations
  • Xanthine Oxidase
  • Aldehyde Oxidase