Wang Xiaoyan, Yang Zhen, Su Feifei, Li Jin, Boadi Evans Owusu, Chang Yan-Xu, Wang Hui
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
Tianjin Key Laboratory of Phytochemistry and Pharmaceutical Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
Molecules. 2020 Jan 20;25(2):422. doi: 10.3390/molecules25020422.
Thrombin, a key enzyme of the serine protease superfamily, plays an integral role in the blood coagulation cascade and thrombotic diseases. In view of this, it is worthwhile to establish a method to screen thrombin inhibitors (such as natural flavonoid-type inhibitors) as well as investigate their structure activity relationships. Virtual screening using molecular docking technique was used to screen 103 flavonoids. Out of this number, 42 target compounds were selected, and their inhibitory effects on thrombin assayed by chromogenic substrate method. The results indicated that the carbon-carbon double bond group at the C2, C3 sites and the carbonyl group at the C4 sites of flavones were essential for thrombin inhibition, whereas the methoxy and O-glycosyl groups reduced thrombin inhibition. Noteworthy, introduction of OH groups at different positions on flavonoids either decreased or increased anti-thrombin potential. Myricetin exhibited the highest inhibitory potential against thrombin with an IC value of 56 μM. Purposively, the established molecular docking virtual screening method is not limited to exploring flavonoid structure activity relationships to anti-thrombin activity but also usefully discovering other natural active constituents.
凝血酶是丝氨酸蛋白酶超家族的关键酶，在血液凝固级联反应和血栓形成性疾病中发挥着不可或缺的作用。鉴于此，建立一种筛选凝血酶抑制剂（如天然黄酮类抑制剂）并研究其构效关系的方法是很有价值的。利用分子对接技术进行虚拟筛选，对103种黄酮类化合物进行筛选。从中选出42种目标化合物，并用发色底物法测定它们对凝血酶的抑制作用。结果表明，黄酮类化合物C2、C3位的碳碳双键基团和C4位的羰基对凝血酶抑制至关重要，而甲氧基和O-糖基会降低凝血酶抑制作用。值得注意的是，在黄酮类化合物不同位置引入羟基会降低或增加抗凝血酶潜力。杨梅素对凝血酶表现出最高的抑制潜力，IC值为56 μM。有目的地，所建立的分子对接虚拟筛选方法不仅限于探索黄酮类化合物与抗凝血酶活性的构效关系，还能有效地发现其他天然活性成分。
