In Vitro and In Silico Studies to Explore Structural Features of Flavonoids for Aldehyde Oxidase Inhibition

• Published in: Archiv der Pharmazie (Weinheim) 2014-10, Vol.347 (10), p.738-747
• Main Authors: Hamzeh-Mivehroud, Maryam, Rahmani, Seifullah, Feizi, Mohammad-Ali Hosseinpour, Dastmalchi, Siavoush, Rashidi, Mohammad-Reza
• Format: Article
• Language: English
• Subjects: Aldehyde oxidase; Aldehyde Oxidase - antagonists & inhibitors; Aldehyde Oxidase - chemistry; Aldehyde Oxidase - metabolism; Animals; Computer-Aided Design; Drug Design; Enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Flavonoids - chemistry; Flavonoids - pharmacology; Liver - drug effects; Liver - enzymology; Male; Molecular docking; Molecular Dynamics Simulation; Molecular Structure; Protein Conformation; QSAR; Quantitative Structure-Activity Relationship; Rats, Sprague-Dawley; Vanillin
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201400076

Aldehyde oxidase (AO), an important enzyme in the biotransformation of drugs and xenobiotics, is inhibited by flavonoids. This enzyme can metabolize both aldehydes and N‐heterocycles. In this work, a set of 15 flavonoids was assessed for inhibitory activity on the AO oxidation of vanillin as an aldehyde substrate. Spectrophotometrically determined IC50 values showed that myricetin, quercetin, and epicatechin were the most potent inhibitors. The results also revealed that the inhibition of vanillin oxidation by flavonoids was stronger than that of phenanthridine oxidation (an N‐heterocyclic substrate) as reported previously. In order to investigate the important structural features responsible for the inhibitory effects of the studied flavonoids, a quantitative structure–activity relationship (QSAR) analysis was performed. This study showed that the size of the flavonoids was the most important factor inversely affecting their potencies. The QSAR model can be used more broadly to predict the AO inhibitory activity of flavonoid‐like structures for application in food–drug and drug–drug interaction studies. Flavonoids influence the biotransformation of drugs by inhibiting aldehyde oxidase (AO), leading to many drug–drug/drug–food interactions. A set of 15 flavonoids was studied for their ability to inhibit the AO oxidation of vanillin. Myricetin, quercetin, and epicatechin were shown to be the most potent AO inhibitors. QSAR analysis revealed that the size of the flavonoids was the most important factor affecting inhibition.