Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation
Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation
复制标题
天然抗癌活性化合物金雀花碱N-异黄酮的药代动力学、组织分布及成药性预测与计算机模拟相结合
DOI：
10.1248/bpb.b20-00004
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发表时间：
2020-06-01
影响因子：
2
通讯作者：
Zhong, Youquan
中科院分区：
文献类型：
--
作者：
Chen, Fangmei;Yin, Xiaoying;Zhong, Youquan
野靛碱N-亚甲基-（5，7-二羟基-4 '-甲氧基）-野靛碱（Cytisine N-methylene-（5，7-dihydroxy-4'-methoxy）-cytisine，CNF 2）是从中药苦豆子中分离得到的一个新化合物。初步的药效学研究表明其具有抑制乳腺癌细胞转移的活性。本研究考察了CNF 2在大鼠体内的药代动力学、绝对生物利用度和组织分布，并结合计算机辅助技术预测CNF 2的可药用性。采用分子对接技术检测CNF 2与乳腺癌靶点人表皮生长因子受体2（HER 2）的结合位点。然后，利用ACD/Percepta软件，基于定量构效关系（QSAR）对CNF 2的可药用性进行了预测。最后，采用高效液相色谱法研究了CNF 2在大鼠体内的药代动力学和组织分布。预测和实验结果表明，与阳性对照HER 2抑制剂SYR 127063相比，CNF 2与HER 2的结合亲和力更强，提示其药效更强; CNF 2的结构符合Lipinski's Rule of Five，具有良好的药物相似性。CNF 2在大鼠体内停留时间小于4 h，代谢速率较快，但CNF 2在大鼠体内的绝对生物利用度为6.6%，主要分布在胃、肠和肺组织中，含量分别为401.20、144.01和245.82 μ g/g。本研究构建了活性化合物的快速筛选和初步评价方法，为该类化合物的开发和深入研究提供了重要参考。
Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bio-availability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 mu g/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.