Anti-inflammatory drugs as new inhibitors to xanthine oxidase: In vitro and in silico approach

Abstract

The two important targets to treat gout disease are (1) control the hyperuricemia by the inhibition of Xanthine Oxidase (XO) and (2) treatment of acute attacks of gout by the use of anti-inflammatory drugs. It is important to distinguish between therapy to manage hyperuricemia and to reduce acute inflammation. While reducing hyperuricemia is resolved very slowly with available drugs, gout symptoms like pain and inflammation may become persistent. The objective of this study is to find a relevant treatment with a beneficial double effect. (1) As an anti-inflammatory, analgesic, and antipyretic effect and (2) as XO inhibitory effect, which is the main objective of this study. We investigated the effect of five non-steroidal anti-inflammatory drugs (NSAIDs) against human and bovine milk xanthine oxidases (HXO and BXO) using the double enzyme detection method (DED) and molecular docking with the Autodock vina program. in vitro results show that the NSAIDs give an important inhibition to HXO and BXO with an IC₅₀ of 2.04 ± 0.13 μg/ml, 2.75 ± 0.23 μg/ml, 1.45 ± 0.19 μg/ml, 0.31 ± 0.13 μg/ml and 1.27 ± 0.11 μg/ml, for HXO, and 2.96 ± 0.27 μg/ml, 9.46 ± 0.13 μg/ml, 6.21 ± 1.17 μg/ml, 0.83 ± 0.11 μg/ml, and 3.48 ± 0.13 μg/ml, for BXO, for respectively, Naproxen, Ibuprofen, Diclofenac, Indomethacin, and Celecoxib. Testing the inhibitory activity of these drugs on both XOs shows an important inhibition, especially from Indomethacin, which could be a promising lead compound for reducing acute inflammation and at the same time controlling hyperuricemia.

Keywords: Autodock vina; Gout; Molecular docking; Non-steroidal anti-inflammatory drugs; Xanthine oxidase.