In silico design and synthesis of targeted rutin derivatives as xanthine oxidase inhibitors

Abstract

Background: Xanthine oxidase is an important enzyme of purine catabolism pathway and has been associated directly in pathogenesis of gout and indirectly in many pathological conditions like cancer, diabetes and metabolic syndrome. In this research rutin, a bioactive flavonoid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase.

Objective: To develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential.

Method: In this report, we designed and synthesized rutin derivatives hybridized with hydrazines to form hydrazides and natural acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.

Results: The enzyme kinetic studies performed on rutin derivatives showed a potential inhibitory effect on XO ability in competitive manner with IC₅₀ value ranging from 04.708 to 19.377 µM and RU3a ₃ was revealed as most active derivative. Molecular simulation revealed that new rutin derivatives interacted with the amino acid residues PHE798, GLN1194, ARG912, GLN 767, ALA1078 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential.

Conclusion: Taking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.

Keywords: Antioxidant; Molecular docking; Rutin; Xanthine oxidase.

Fig. 1

Design strategy for the development of rutin derivatives

Scheme 1

Synthesis of rutin derivatives

Fig. 2

3D pose of RU3a₃ inside the binding pocket

Fig. 3

2D pose of RU3a₃ inside the binding pocket

Fig. 4

3D pose of RU3a₃ showing hydrogen bonding (yellow) with GLN1194, ARG 912, GLY795, GLN 585 and π–π bonding (blue) with PHE798

Fig. 5

3D pose of RU3a₁ inside the binding pocket

Fig. 6

2D pose of RU3a₁ inside the binding pocket

Fig. 7

3D pose of RU3a₁ showing hydrogen bonding with GLN 1194, MET1038 and GLY 1039

Fig. 8

3D pose of rutin showing hydrogen bonding with GLN 1194 and MET1038

Fig. 9

3D pose of allopurinol showing hydrogen bonding with GLN 1194

Fig. 10

Structure activity relationship (SAR) of synthesized compounds

Fig. 11

Lineweaver–Burk plot for RU3a₃ against different concentrations

Fig. 12

Michaelis–Menten curve for RU3a₃ at different concentrations