Docking study of quercetin derivatives on inducible Nitric Oxide Synthase and prediction of their absorption and distribution properties

Abstract

Some flavonoids, including quercetin, were reported to show inhibitory activities against inducible Nitric Oxide Synthase (iNOS), an isoenzyme responsible for nitric oxide formation. The objectives of this research are to obtain binding and inhibitory parameters of some quercetin derivatives on iNOS by means of docking method and prediction of their oral absorption and distribution properties. Seven selected flavonoids and ten quercetin derivatives were used as ligands for the study. The iNOS structure was obtained from Brookhaven protein databank (PDB ID: 1M9T) and docking study was performed using ArgusLab free software. Binding energy (ΔGbind) and hydrogen bond were used to analyze interactions between ligands and active site of iNOS. The PreADMET on line program was used to predict the oral absorption and distribution properties including permeability for Caco-2 cell, HIA (human intestinal absorption) and plasma protein binding. The results showed that hydrogen bonds formed between flavonoids and iNOS always involved the amide groups of glycine (A365) and trypsine (A366) residues in iNOS active site and 4-carbonyl group of flavonoids. In the docked form, the planar region of A-ring of flavonoids oriented to the heme plane of iNOS. Thus the 4-carbonyl group and planar region of A-ring of flavonoids are essential for the binding with iNOS. Linear regression of binding energy versus negative logarithm of IC50 of flavonoids gave an equation of -log IC50 = -0.399 ΔGbind- 5.608 (R2 = 0.686; p<0.01) and predicted IC50 of Quercetin was 76.79 μM. The human intestinal absorption (HIA) and Caco-2 cell permeability values of quercetin were 63.5% and 3.4 nm sec-1 while its plasma protein binding was 93.2%, respectively. Quercetin-3-O-acetate, 6,8-dichloroquercetin-3-(9-acetate and 6-bromoquercetin-3-(3-acetate showed lower predicted IC50 and better absorption and distribution properties than quercetin. © 2010 Asian Network for Scientific Information.