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

Torres, Rhonda A.; Korzekwa, Kenneth R.; McMasters, Daniel R.; Fandozzi, Christine; Jones, Jeffrey P.

doi:10.1021/jm0703690

Cited by 65 publications

(87 citation statements)

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%

“…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%

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Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Dalvie

Sun²,

Xiang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, -stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (E LUMO )], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642-4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and E LUMO ). Overall, the structuremetabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structuremetabolism relationships of other AO substrates.

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Section: Introductionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Dalvie

Sun²,

Xiang³

et al. 2012

Drug Metab Dispos

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“…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%

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

et al. 2012

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ABSTRACT:Aldehyde oxidase (AO) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. AO is active as a homodimer, and each 150-kDa monomer binds two distinct [2Fe2S] clusters, FAD, and the molybdenum cofactor. AO has an important role in the metabolism of drugs based on its broad substrate specificity oxidizing aromatic aza-heterocycles, for example, was obtained with a purity of 95% and a yield of 50 g/l E. coli culture. Site-directed mutagenesis of the hAOX1 cDNA allowed the purification of protein variants bearing the amino acid changes R802C, R921H, N1135S, and H1297R, which correspond to some of the identified SNPs. The hAOX1 variants were purified and compared with the wild-type protein relative to activity, oligomerization state, and metal content. Our data show that the mutation of each amino acid residue has a variable impact on the ability of hAOX1 to metabolize selected substrates. Thus, the human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. Our results indicate that the presence of these allelic variants should be considered for the design of future drugs.

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“…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%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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

Cited by 65 publications

References 28 publications

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

Mitigating Heterocycle Metabolism in Drug Discovery

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