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Use of Density Functional Calculations To Predict the Regioselectivity of Drugs and Molecules Metabolized by Aldehyde Oxidase

Rhonda A. Torres,*^†^‡ Kenneth R. Korzekwa,*^§ Daniel R. McMasters,^† Christine M. Fandozzi,^§ and Jeffrey P. Jones*^‡

Department of Molecular Systems, Merck Research Laboratories, Rahway, New Jersey 07065, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19468, and Department of Chemistry, Washington State University, Pullman, Washington 99164

J. Med. Chem., 2007, 50 (19), pp 4642–4647

DOI: 10.1021/jm0703690

Publication Date (Web): August 25, 2007

To whom correspondence should be addressed. For R.A.T.: phone, 509-335-1516; e-mail, rhonda.torres@yahoo.com. For K.R.K.: e-mail, korzekwa@allchemie.net. For J.P.J.: phone, 509-335-5983; e-mail, jpj@wsu.edu.

†

Department of Molecular Systems, Merck Research Laboratories.

‡

Washington State University.

Department of Drug Metabolism, Merck Research Laboratories.

Abstract

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.

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