Andrographolide binds to ATP-binding pocket of VEGFR2 to impede VEGFA-mediated tumor-angiogenesis
Andrographolide binds to ATP-binding pocket of VEGFR2 to impede VEGFA-mediated tumor-angiogenesis
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DOI：
10.1038/s41598-019-40626-2
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发表时间：
2019-03-11
影响因子：
4.6
通讯作者：
Sa, Gaurisankar
中科院分区：
文献类型：
--
作者：
Kajal, Kirti;Panda, Abir K.;Sa, Gaurisankar
血管发生和血管生成是血管形成的过程。血管的进化是为了将营养和氧气分配到远处的器官。这些血管对于受伤组织的生长和修复至关重要。在肿瘤状况期间，血管生长发生不平衡，导致新血管生成。新血管生成是肿瘤形成的主要推动者。肿瘤细胞分泌促血管生成因子 VEGFA，该因子与内皮细胞表面的 VEGFR2 结合并触发新血管的形成。为了抑制肿瘤血管生成，筛选了一种生理安全的小分子抑制剂，它可以与 VEGFR2 激酶结构域相互作用并抑制其活性。分子对接模块和生化分析确定穿心莲内酯是与 VEGFR2 的 ATP 结合袋结合并抑制其激酶活性的最佳对接分子之一。因此，为了更彻底地开发安全的 VEGFR2 抑制剂，穿心莲内酯被重新用于抑制肿瘤血管生成并减轻肿瘤负荷。
Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.