Abstract
BackgroundXanthine 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.ObjectiveTo develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential.MethodIn 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.ResultsThe 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 RU3a3 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.ConclusionTaking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.
Highlights
Xanthine oxidase (XO) having molecular weight of around 300 kDa is oxidoreductase enzyme represented in the form of a homodimer
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 RU3a3 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
Summary
Xanthine oxidase (XO) having molecular weight of around 300 kDa is oxidoreductase enzyme represented in the form of a homodimer Both the monomers of XO are almost identical and each of them contains three domains namely (a) molybdopterin (Mo-pt) domain at the C-terminal having 4 redox centers where oxidation takes place (b) a flavin adenine dinucleotide (FAD) domain at the centre generally considered as binding site domain and (c) 2[Fe–S]/iron sulfur domain at the N-terminal [1–3]. Considering the life threatening side effects like Stevens–Johnsons syndrome caused by allopurinol use, scientists turned their interest into nonpurine XO inhibitors and an immense accomplishment has been received in this direction with development of new drug Febuxostat [22–25]. This non-purine candidate produced minor and non-life threatening adverse effects in comparison to Allopurinol [26–29]. A bioactive flavonoid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
