From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions

Cruciani, Gabriele; Milani, Nicoló; Benedetti, Paolo; Lepri, Susan; Cesarini, Lucia; Baroni, Massimo; Spyrakis, Francesca; Tortorella, Sara; Mosconi, Edoardo; Goracci, Laura

doi:10.1021/acs.jmedchem.7b01552

Cited by 29 publications

(34 citation statements)

References 51 publications

(113 reference statements)

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“…5. The meta-O-linked EDGs in XK-469 (2-[4-(7-chloroquinoxalin-2-yl) oxyphenoxy]propanoate) (Anderson et al, 2005;Hutzler et al, 2012) and VU0409106 [3-fluoro-N-(4-methyl-2-thiazolyl)-5-(5-pyrimidinyloxy) benzamide] (Morrison et al, 2012), or the meta-N-linked EDG in example 2, and compounds 20 (Lepri et al, 2017;Cruciani et al, 2018) and 30 (Glatthar et al, 2016) made these compounds more susceptible to AO metabolism (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

Xiao

Gao

et al. 2018

Drug Metab Dispos

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Some quinoline-containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-Substituted quinoline triazolopyridine analogs were synthesized to understand the electron-donating and steric hindrance effects on AO-mediated metabolism. Metabolic stability studies for these quinoline analogs were carried out in liver cytosol from mice, rats, cynomolgus monkeys, and humans. Several 3-N-substituted analogs were found to be unstable in monkey liver cytosolic incubations (half-life, <10 minutes), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies. Mono-oxygenation on the quinoline ring was identified by liquid chromatography tandem mass spectrometry. Metabolite formation was inhibited by the AO inhibitors menadione and raloxifene, but not by the xanthine oxidase inhibitor allopurinol. It was found that small electron-donating groups at the 3-quinoline moiety made the analogs more susceptible to AO metabolism, whereas large 3-substituents could reverse the trend. Although species differences were observed, this trend was applicable to all species tested. Small electron-donating substituents at the 3-quinoline moiety increased both affinity (decreased Michaelis constant) and maximum velocity toward AO in kinetic studies, whereas large substituents decreased both parameters probably as a result of steric hindrance. Based on our analysis, a common structural feature with high AO liability was proposed. Our finding could provide useful information for chemists to minimize potential AO liability when designing quinoline analogs.

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Section: Discussionmentioning

confidence: 99%

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

Xiao

Gao

et al. 2018

Drug Metab Dispos

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“…Future clinical studies would be needed to determine whether these interactions occur in vivo. To date, studies have been reported on AOX1 protein structure-drug metabolism relationships to predict human AOX1 substrates (Lepri et al, 2017;Cruciani et al, 2018), but limited information on human AOX1 structure-enzyme inhibitor relationships determined based on the crystal structure of human AOX1 (Takaoka et al, 2018;Deris-Abdolahpour et al, 2019). The molecular-docking approach developed in this study, by virtue of its consistent performance and the ability it allows for meaningful comparative analyses of chemical inhibitors, provides a robust in silico framework for future investigation of the binding of chemical inhibitors with AOX1.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues

Chen

Austin-Muttitt

Zhang

et al. 2019

J Pharmacol Exp Ther

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Tamoxifen, raloxifene, and nafoxidine are selective estrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drugmetabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogs was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank order in the potency (based on IC 50 values) of AOX1 inhibition by SERMs was raloxifene. bazedoxifene ∼ lasofoxifene. tamoxifen. acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular-docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular-docking analyses provide new insights into the interaction between SERMs and AOX1. SIGNIFICANCE STATEMENT Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective estrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular-docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals.

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“…The three-dimensional (3D) structures of the lowest energy conformations of the 5 lead candidates were used as input data in the MetaSite 6.0 program [47] (Molecular Discovery, Borehamwood, Hertfordshire-United Kingdom). For each compound, twenty constituents were generated by the program.…”

Section: Metabolic Predictionmentioning

confidence: 99%

Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity

Menezes

Viana

Muratov

et al. 2022

CIMB

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Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.

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From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions

Cited by 29 publications

References 51 publications

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues

Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity

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