Repository of Research and Investigative Information

Repository of Research and Investigative Information

Kurdistan University of Medical Sciences

Effects of Phenothiazines on Aldehyde Oxidase Activity Towards Aldehydes and N-Heterocycles: an In Vitro and In Silico Study

(2019) Effects of Phenothiazines on Aldehyde Oxidase Activity Towards Aldehydes and N-Heterocycles: an In Vitro and In Silico Study. European Journal of Drug Metabolism and Pharmacokinetics.

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Abstract

Background: Aldehyde oxidase (AOX) is an important molybdenum-containing enzyme with high similarity with xanthine oxidase (XO). AOX involved in the metabolism of a large array of aldehydes and N-heterocyclic compounds and its activity is highly substrate-dependent. Objectives: The aim of this work was to study the effect of five important phenothiazine drugs on AOX activity using benzaldehyde and phenanthridine as aldehyde and N-heterocyclic substrates, respectively. Methods: The effect of trifluperazine, chlorpromazine, perphenazine, thioridazine and promethazine on rat liver AOX was measured spectrophotometrically. To predict the mode of interactions between the studied compounds and AOX, a combination of homology modeling and a molecular docking study was performed. Results: All phenothiazines could inhibit AOX activity measured either by phenanthridine or benzaldehyde with almost no effect on XO activity. In the case of benzaldehyde oxidation, the lowest and highest half-maximal inhibitory concentration (IC 50 ) values were obtained for promethazine (IC 50 = 0.9 µM), and trifluoperazine (IC 50 = 3.9 µM), respectively; whereas perphenazine (IC 50 = 4.3 µM), and trifluoperazine (IC 50 = 49.6 µM) showed the strongest and weakest inhibitory activity against AOX-catalyzed phenanthridine oxidation, respectively. The in silico findings revealed that the binding site of thioridazine is near the dimer interference, and that hydrophobic interactions are of great importance in all the tested phenothiazines. Conclusion: The five studied phenothiazine drugs showed dual inhibitory effects on AOX activity towards aldehydes and N-heterocycles as two major classes of enzyme substrates. Most of the interactions between the phenothiazine-related drugs and AOX in the binding pocket showed a hydrophobic nature. © 2018, Springer Nature Switzerland AG.

Item Type: Article
Keywords: aldehyde oxidase; benzaldehyde; chlorpromazine; perphenazine; phenanthridine derivative; phenothiazine derivative; promethazine; thioridazine; trifluoperazine; aldehyde; aldehyde oxidase; enzyme inhibitor; heterocyclic compound, animal tissue; Article; computer model; drug binding site; drug effect; enzyme activity; enzyme inhibition; enzyme substrate; hydrophobicity; IC50; in vitro study; male; molecular docking; nonhuman; oxidation; rat; spectrophotometry; structural homology; amino acid sequence; animal; antagonists and inhibitors; binding site; chemistry; computer simulation; enzyme activation; metabolism; physiology; procedures; protein secondary structure; Wistar rat, Aldehyde Oxidase; Aldehydes; Amino Acid Sequence; Animals; Binding Sites; Computer Simulation; Enzyme Activation; Enzyme Inhibitors; Heterocyclic Compounds; Male; Molecular Docking Simulation; Phenothiazines; Protein Structure, Secondary; Rats; Rats, Wistar
Page Range: pp. 275-286
Journal or Publication Title: European Journal of Drug Metabolism and Pharmacokinetics
Volume: 44
Number: 2
Publisher: Springer-Verlag France
Identification Number: 10.1007/s13318-018-0514-6
ISSN: 03787966
Depositing User: مهندس جمال محمودپور
URI: http://eprints.muk.ac.ir/id/eprint/2024

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