黄嘌呤氧化酶
化学
生物化学
酶
次黄嘌呤
非竞争性抑制
活动站点
对接(动物)
高尿酸血症
超氧化物
超氧化物歧化酶
非布索坦
嘌呤
立体化学
活性氧
药理学
尿酸
生物
医学
护理部
作者
Rosario Rullo,Carmen Cerchia,Rosarita Nasso,Virgilio Romanelli,Emmanuele De Vendittis,Mariorosario Masullo,Antonio Lavecchia
出处
期刊:Antioxidants
[MDPI AG]
日期:2023-03-28
卷期号:12 (4): 825-825
被引量:5
标识
DOI:10.3390/antiox12040825
摘要
Xanthine oxidase (XO) is a flavoprotein catalysing the oxidation of hypoxanthine to xanthine and then to uric acid, while simultaneously producing reactive oxygen species. Altered functions of XO may lead to severe pathological diseases, including gout-causing hyperuricemia and oxidative damage of tissues. These findings prompted research studies aimed at targeting the activity of this crucial enzyme. During the course of a virtual screening study aimed at the discovery of novel inhibitors targeting another oxidoreductase, superoxide dismutase, we identified four compounds with non-purine-like structures, namely ALS-1, -8, -15 and -28, that were capable of causing direct inhibition of XO. The kinetic studies of their inhibition mechanism allowed a definition of these compounds as competitive inhibitors of XO. The most potent molecule was ALS-28 (Ki 2.7 ± 1.5 µM), followed by ALS-8 (Ki 4.5 ± 1.5 µM) and by the less potent ALS-15 (Ki 23 ± 9 µM) and ALS-1 (Ki 41 ± 14 µM). Docking studies shed light on the molecular basis of the inhibitory activity of ALS-28, which hinders the enzyme cavity channel for substrate entry consistently with the competitive mechanism observed in kinetic studies. Moreover, the structural features emerging from the docked poses of ALS-8, -15 and -1 may explain the lower inhibition power with respect to ALS-28. All these structurally unrelated compounds represent valuable candidates for further elaboration into promising lead compounds.
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