2007
DOI: 10.1021/jm0703690
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Use of Density Functional Calculations To Predict the Regioselectivity of Drugs and Molecules Metabolized by Aldehyde Oxidase

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… Show more

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Cited by 64 publications
(87 citation statements)
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References 28 publications
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“…Ghafourian and Rashidi (2001) have reported on structure-activity relationship studies of phthalazine and quinazoline derivatives and the influence of substituents on AOmediated oxidation. The findings from these studies are consistent with a nucleophilic attack on an electron-deficient sp 2 -hybridized carbon atom by AO (Hille, 2005;Torres et al, 2007) with electrondeficient groups favoring the oxidation reaction. Likewise, the role of hydrophobicity as well as electronic properties in determining their AO-mediated catalysis has also been demonstrated (Krenitsky et al, 1972;Hall and Krenitsky, 1986;Beedham et al, 1990).…”
Section: Introductionsupporting
confidence: 70%
See 1 more Smart Citation
“…Ghafourian and Rashidi (2001) have reported on structure-activity relationship studies of phthalazine and quinazoline derivatives and the influence of substituents on AOmediated oxidation. The findings from these studies are consistent with a nucleophilic attack on an electron-deficient sp 2 -hybridized carbon atom by AO (Hille, 2005;Torres et al, 2007) with electrondeficient groups favoring the oxidation reaction. Likewise, the role of hydrophobicity as well as electronic properties in determining their AO-mediated catalysis has also been demonstrated (Krenitsky et al, 1972;Hall and Krenitsky, 1986;Beedham et al, 1990).…”
Section: Introductionsupporting
confidence: 70%
“…To this end, the metabolic stability of zoniporide and its analogs was determined by estimating their half-lives in the human S9 fraction and the effect of variation in zoniporide structure on its AO-mediated biotransformation to M1 was investigated. The differences were rationalized by comparing their half-lives with cLogD and electrophilicity parameters (partial atomic charges and E LUMO ), and the energies of formation of tetrahedral intermediates as reported by Torres et al (2007). In addition, zoniporide and its selected analogs were docked into the AO homology model in an attempt to explore the pattern of interactions between zoniporide and the active site residues in AO.…”
Section: Introductionmentioning
confidence: 99%
“…Two of the SNPs resulted in FM and one in PM individuals. hAOX1 is an important enzyme responsible for the metabolism of a number of drugs containing aldehydes and the more prevalent nitrogen heterocycles (Kitamura et al, 2006;Torres et al, 2007). The fraction of drugs metabolized by hAOX1 is likely to increase over the next decade.…”
Section: Hartmann Et Almentioning
confidence: 99%
“…55 The cyclooxygenase (COX-1/2) inhibitors sudoxicam (86) and meloxicam (87) have the same structure except that meloxicam has a methyl group at the C-5 position of the thiazole ring. P450 mediated oxidation of sudoxicam occurred to form a reactive epoxide 88, which after hydrolysis produced the protoxin acylthiourea 89.…”
Section: ■ Heteroaromatic Compoundsmentioning
confidence: 99%