Validation of in Silico Docking Analysis of Oligophenylpropanoids to Xanthine Oxidase by Correlation with in Vitro Bioassay and Its Application to Phlorotannins

Sheau Ling Ho,Hyeung-Rak Kim,Sheng-Fa Tsai,Ching-Ting Lin,Shoei-Sheng Lee

doi:10.11648/j.jddmc.20200601.11

Abstract

The oligo-phenylpropanoids 1−7, isolated from Hyptis rhombodes, 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 ΔG) mode, showed good correlation with the IC50 values. That the compounds possessing 7′-Z configuration had much better inhibitory activity than those 7′-E 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 ΔG) 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 Ecklonia genus, the common edible seaweeds such as E. cava and E. stolonifera 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

Introduction

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

Methods

Results

Conclusion