Li Jing, Zhou Nan, Luo Kun, Zhang Wei, Li Xinru, Wu Chuanfang, Bao Jinku
College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China.
Int J Mol Sci. 2014 Sep 11;15(9):15994-6011. doi: 10.3390/ijms150915994.
Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (-62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217- and ZINC08254138-VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (-54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was -49.37, -43.32, and -32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.
血管生成是指从现有血管生长出新的毛细血管，这些血管供应氧气和营养物质，并为免疫监视提供通道。就过度血管生成而言，异常的血管生长是癌症、炎症和眼部疾病的一个标志。主导血管生成过程的血管内皮生长因子受体2（VEGFR-2）已促使治疗性抑制剂获得批准，并正成为抗血管生成药物的一个有前景的靶点。尽管取得了这些成功，但目前VEGFR-2阻滞剂的临床应用比预期更具挑战性。以阿昔替尼作为参考药物，在我们的研究中，我们从天然衍生物中发现了三种有效的VEGFR-2抑制剂（ZINC08254217、ZINC08254138和ZINC03838680）。当与VEGFR-2对接时，这三种抑制剂中的每一种都获得了比阿昔替尼（-62.11）更好的网格分数。分子动力学模拟表明，ZINC08254217-和ZINC08254138-VEGFR-2复合物比阿昔替尼更稳定。与阿昔替尼的结合自由能（-54.68 kcal/mol）相似，ZINC03838680、ZINC08254217和ZINC（此处原文有误，应为ZINC08254138）08254138的结合自由能分别为-49.37、-43.32和-32.73 kcal/mol。这些结果表明，这三种化合物可能是抗血管生成的候选药物，与阿昔替尼具有相当的VEGFR-2结合亲和力。因此，我们研究中的发现能够为发现有效的抗血管生成疗法提供有价值的信息。
