Saeed Mohamed E M, Kadioglu Onat, Seo Ean-Jeong, Greten Henry Johannes, Brenk Ruth, Efferth Thomas
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Biomedical Sciences Institute Abel Salazar, University of Porto, Porto, Portugal Heidelberg School of Chinese Medicine, Heidelberg, Germany.
Anticancer Res. 2015 Apr;35(4):1929-34.
BACKGROUND/AIM: The antimalarial drug artemisinin has been shown to exert anticancer activity through anti-angiogenic effects. For further drug development, it may be useful to have derivatives with improved anti-angiogenic properties.
We performed molecular docking of 52 artemisinin derivatives to vascular endothelial growth factor receptors (VEGFR1, VEGFR2), and VEGFA ligand using Autodock4 and AutodockTools-1.5.7.rc1 using the Lamarckian genetic algorithm. Quantitative structure-activity relationship (QSAR) analyses of the compounds prepared by Corina Molecular Networks were performed using the Molecular Operating Environment MOE 2012.10.
A statistically significant inverse relationship was obtained between in silico binding energies to VEGFR1 and anti-angiogenic activity in vivo of a test-set of artemisinin derivatives (R=-0.843; p=0.035). This served as a control experiment to validate molecular docking predicting anti-angiogenc effects. Furthermore, 52 artemisinin derivatives were docked to VEGFR1 and in selected examples also to VEGFR2 and VEGFA. Higher binding affinities were calculated for receptors than for the ligand. The best binding affinities to VEGFR1 were found for an artemisinin dimer, 10-dihydroartemisinyl-2-propylpentanoate, and dihydroartemisinin α-hemisuccinate sodium salt. QSAR analyses revealed significant relationships between VEGFR1 binding energies and defined molecular descriptors of 35 artemisinins assigned to the training set (R=0.0848, p<0.0001) and 17 derivatives assigned to the test set (R=0.761, p<0.001).
Molecular docking and QSAR calculations can be used to identify novel artemisinin derivatives with anti-angiogenic effects.
背景/目的：抗疟药物青蒿素已被证明可通过抗血管生成作用发挥抗癌活性。为了进一步开展药物研发，具有改善抗血管生成特性的衍生物可能会有所帮助。
我们使用拉马克遗传算法，通过Autodock4和AutodockTools - 1.5.7.rc1对52种青蒿素衍生物与血管内皮生长因子受体（VEGFR1、VEGFR2）以及VEGFA配体进行了分子对接。使用Molecular Operating Environment MOE 2012.10对Corina Molecular Networks制备的化合物进行了定量构效关系（QSAR）分析。
在一组青蒿素衍生物的体内抗血管生成活性与对VEGFR1的计算机模拟结合能之间获得了具有统计学意义的负相关关系（R = -0.843；p = 0.035）。这作为验证预测抗血管生成作用的分子对接的对照实验。此外，将52种青蒿素衍生物与VEGFR1进行对接，在选定的例子中还与VEGFR2和VEGFA进行对接。计算得出受体的结合亲和力高于配体。发现青蒿素二聚体、10 - 二氢青蒿素基 - 2 - 丙基戊酸酯和二氢青蒿素α - 半琥珀酸钠盐对VEGFR1的结合亲和力最佳。QSAR分析揭示了VEGFR1结合能与分配给训练集的35种青蒿素（R = 0.0848，p < 0.0001）和分配给测试集的17种衍生物（R = 0.761，p < 0.001）的特定分子描述符之间的显著关系。
分子对接和QSAR计算可用于鉴定具有抗血管生成作用的新型青蒿素衍生物。
