Structural evidence of quercetin multi-target bioactivity: A reverse virtual screening strategy
Structural evidence of quercetin multi-target bioactivity: A reverse virtual screening strategy
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DOI：
10.1016/j.ejps.2017.06.028
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发表时间：
2017-08-30
影响因子：
4.6
通讯作者：
Abin-Carriquiry, Juan A.
中科院分区：
文献类型：
--
作者：
Carvalho, Diego;Paulino, Margot;Abin-Carriquiry, Juan A.
普遍存在的类黄酮槲皮素被广泛认为具有多种生物和健康促进作用，如抗癌、抗炎和细胞保护活性。槲皮素和类似化合物在预防各种氧化应激相关病理方面的治疗潜力通常归因于它们的直接抗氧化特性。然而，越来越多的证据表明，槲皮素也能够与多种细胞靶点相互作用，影响多种信号通路的活性。尽管已经有许多确定的蛋白质靶点，如磷脂酰肌醇3激酶和黄嘌呤氧化酶，但对槲皮素及其靶点空间的潜在作用机制仍然缺乏全面的了解。在目前的工作中，我们采用了基于配体相似性（shaft）和靶标结构（idTarget， LIBRA）的反向筛选策略，从而获得了一组预测的蛋白质靶标候选物。此外，使用这种方法，我们在预测靶标中证实了大量先前实验测试的候选物，支持这种筛选方法的适用性。值得注意的是，所有预测的候选靶标都属于两个主要的蛋白质家族，蛋白激酶和聚[adp -核糖]聚合酶。它们还包括在同一信号通路的不同点或相互连接的信号通路中参与的关键蛋白质，支持槲皮素的多效性、多层次和潜在的协同作用机制。在这种情况下，我们强调槲皮素在炎症、神经退行性疾病和癌症等疾病的治疗潜力的广泛目标概况的价值。
The ubiquitous flavonoid quercetin is broadly recognized for showing diverse biological and health-promoting effects, such as anti-cancer, anti-inflammatory and cytoprotective activities. The therapeutic potential of quercetin and similar compounds for preventing such diverse oxidative stress-related pathologies has been generally attributed to their direct antioxidant properties. Nevertheless, accumulated evidence indicates that quercetin is also able to interact with multiple cellular targets influencing the activity of diverse signaling pathways. Even though there are a number of well-established protein targets such as phosphatidylinositol 3 kinase and xanthine oxidase, there remains a lack of a comprehensive knowledge of the potential mechanisms of action of quercetin and its target space. In the present work we adopted a reverse screening strategy based on ligand similarity (SHAFTS) and target structure (idTarget, LIBRA) resulting in a set of predicted protein target candidates. Furthermore, using this method we corroborated a broad array of previously experimentally tested candidates among the predicted targets, supporting the suitability of this screening approach. Notably, all of the predicted target candidates belonged to two main protein families, protein kinases and poly [ADP-ribose] polymerases. They also included key proteins involved at different points within the same signaling pathways or within interconnected signaling pathways, supporting a pleiotropic, multilevel and potentially synergistic mechanism of action of quercetin. In this context we highlight the value of quercetin's broad target profile for its therapeutic potential in diseases like inflammation, neurodegeneration and cancer.