Session: Bioinorganic Chemistry:

Gout is a chronic, inflammatory condition due to slow urate metabolism. The xanthine oxidase inhibitors, such as allopurinol and febuxostat, are recommended to reduce the uric acid level and prevent gout to attack in adult patients.
The emerging new generation of xanthine inhibitor, FYX051, displays a high cost effectiveness compared with febuxostat therapy in chronic gout patients.However, the metabolites of N-oxides from FYX-051 (Topiroxostat) could potentially have adverse effect on patients with severe renal impairment if they have been taking an oral injection for a long period of time as shown in the report on the deliberation results for evaluation of FYX051 (Topiroxostat).Therefore, it is desirable to design new inhibitors without 1,2,4-triazole C=N components.
Here, we computationally designed several modified inhibitors with 1,2,4-triazole ring being replaced by furan, thiophene, pyrrole, selephene. The computationally results indicate that the binding energy of new inhibitors with xanthine oxidase active site is slightly smaller than that from FYX051. In addition, the new designed inhibitors will also help to probe the protonation state of glutamate 832, which is proposed to contribute the energy stabilization of inhibitors by hydrogen bonding.

Chao Dong

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