Abstract
The oligo-phenylpropanoids 1−7, isolated from <i>Hyptis rhombodes</i>, have been found to possess potent inhibitory activity against xanthine oxidase (EC 1.2.3.2, bovine milk). To rationalize such activity, computer assisted docking of these compounds and allopurinol, a positive control, on the xanthine oxidase was undertaken in this study. The docking scores, obtained by London (trimatch)−refinement (Forcefield Affinity <i>ΔG</i>) mode, showed good correlation with the IC<sub>50</sub> values. That the compounds possessing 7′-<i>Z</i> configuration had much better inhibitory activity than those 7′-<i>E</i> isomers is well rationalized by this docking study. Virtual screening of eight phlorotannins (8−15) by this refinement mode found good docking scores. The bioassay result of three available ones (9, 12, 13) also indicated the consistency with the docking scores. While refined by Forcefield−London mode, certain inconsistency among the docking score and bioassay result was observed on either phenylpropanoid oligomers or three phlorotannins. Hence the London (trimatch)−refinement (Forcefield−Affinity <i>ΔG</i>) mode is recommended for virtual screening of the related phenolics. Three phlorotannins (11, 14, 15) were found to have better docking score than 6,6'-bieckol (12) and dieckol (13), both showing comparable inhibitory activity against xanthine oxidase to allopurinol, and thus they deserve further study. In addition, as these phlorotannins are rich in the <i>Ecklonia</i> genus, the common edible seaweeds such as <i>E. cava</i> and <i>E. stolonifera</i> are demonstrated to be beneficial to hyperuricemic patients.
Highlights
Xanthine oxidase (XO) is a molybdenum-containing hydroxylase which catalyzes the oxidation of purine substrates, hypoxanthine and xanthine, to yield uric acid and reactive oxygen species [1]
For the molecular docking study, all small molecules except those in the binding side of XO were removed and the template was constructed from the remaining scaffold using the co-crystal structure of salicylate-xanthine oxidase complex as a reference [6], where the substrate binding and oxidation occur at the molybdopterin cofactor (Mo-pt) center
The binding affinity of compounds (1−15) toward xanthine oxidase showed that the interaction associated strongly with certain amino acid residues in the active site such as Arg880, Thr1010, and Glu1261
Summary
Xanthine oxidase (XO) is a molybdenum-containing hydroxylase which catalyzes the oxidation of purine substrates, hypoxanthine and xanthine, to yield uric acid and reactive oxygen species [1]. The excessive production or insufficient elimination of uric acid results in hyperuricemia, which is associated with gout [2]. XO inhibitors have been proven their efficacy in lowering blood uric acid in animal models and clinical application [3]. The development of xanthine oxidase inhibitors has become one of the therapeutic approaches for treating hyperuricemia. Allopurinol, an XO inhibitor, is the most commonly used anti-gout drug in the past decades [3]. Alternatives of allopurinol with potent anti-XO efficacy and less or void of side effects are in medical need
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