Xanthine oxidoreductase inhibition – A review of computational aspect

Abstract

Xanthine Oxidoreductase (XOR) exists in a variety of organisms from bacteria to humans and catalyzes the oxidation of hypoxanthine to xanthine and from xanthine to uric acid. Excessive uric acid could lead to gout and hyperuricemia. In this paper, we have reviewed the recent computational studies on xanthine oxidase inhibition. Computational methods, such as molecular dynamics (molecular mechanics), quantum mechanics, and quantum mechanics/molecular mechanics (QM/MM), have been employed to investigate the binding affinity of xanthine oxidase with synthesized and isolated nature inhibitors. The limitations of different computational methods for xanthine oxidase inhibition studies were also discussed. Implications of the computational approach could be used to help to understand the existing arguments on substrate/product orientation in xanthine oxidase inhibition, which allows designing new inhibitors with higher efficacy.

A multiscale screening strategy for the identification of novel xanthine oxidase inhibitors based on the pharmacological features of febuxostat analogues

“…1a, XO is a homodimer, and each B150 kDa subunit contains three redox domains: one flavin adenine dinucleotide (FAD) cofactor, two iron-sulfur clusters (2Fe/S, N-terminal), and one molybdopterin (Mo-Pt) cofactor (Moco, C-terminal). 17,18 In the catalysis process (Fig. 1b), electrons move from Moco to FAD via 2Fe/S; as for XO, O 2 acts as an electron acceptor to generate two reactive oxygen species (ROS), including superoxide ions (O 2 À ) and hydrogen peroxide (H 2 O 2 ), by receiving electrons.…”

“…In the human body, allopurinol is metabolized to oxypurinol, and oxypurinol cooperates with Mo-Pt to inhibit XO activity. 17 Febuxostat binds to the active site of XO via noncovalent interactions, rather than Mo-Pt, but topiroxostat interacts directly with Mo-Pt to hinder XO catalysis. 22 However, adverse drug reaction (ADR) cases of XOIs have emerged endlessly.…”

Molecular Dockings and Molecular Dynamics Simulations Reveal the Potency of Different Inhibitors against Xanthine Oxidase

“…When the activity of XO in the body is high, the production of uric acid will increase sharply, leading to hyperuricemia and even gout. 1,3,4 Hence, XO is the most important target for the treatment of hyperuricemia, gout, and other related diseases. 6 Allopurinol (the 3D structure is shown in Figure 1c) is a drug that is widely used to treat gout, and it is catalyzed to alloxanthine by xanthine oxidase in vivo.…”

“…Xanthine oxidase (XO, EC1.17.3.2) (Figure a) is an enzyme with low specificity. It can catalyze the formation from hypoxanthine to xanthine (Figure b). − Molybdenum in the enzyme exists in the form of molybdopterin cofactor, which is the active site of the enzyme (Figure a). The overall structure of XO contained a reductive half-reaction where the substrate was oxidatively hydroxylated at the molybdenum center (Figure a).…”

“…The substrate of the enzyme, xanthine, is shown in Figure b. When the activity of XO in the body is high, the production of uric acid will increase sharply, leading to hyperuricemia and even gout. ,, Hence, XO is the most important target for the treatment of hyperuricemia, gout, and other related diseases …”