A Systems Biology-Based Approach to Uncovering Molecular Mechanisms Underlying Effects of Traditional Chinese Medicine Qingdai in Chronic Myelogenous Leukemia, Involving Integration of Network Pharmacology and Molecular Docking Technology.
A Systems Biology-Based Approach to Uncovering Molecular Mechanisms Underlying Effects of Traditional Chinese Medicine Qingdai in Chronic Myelogenous Leukemia, Involving Integration of Network Pharmacology and Molecular Docking Technology.
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基于系统生物学的方法揭示中药青黛治疗慢性粒细胞白血病的分子机制，涉及网络药理学和分子对接技术的整合
DOI：
10.12659/msm.908104
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发表时间：
2018-06-23
期刊：
影响因子：
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通讯作者：
Sun C
中科院分区：
文献类型：
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作者：
Zhou C;Liu L;Zhuang J;Wei J;Zhang T;Gao C;Liu C;Li H;Si H;Sun C
多靶点整体调控方法越来越多地被用于预测中药的主要活性成分和潜在靶点群，并确定其疗效所涉及的机制。青黛是治疗慢性粒细胞白血病（CML）的主要中药，但以往研究尚未明确其治疗CML的复杂活性成分和抗肿瘤靶点。
我们利用Cytoscape软件，根据慢性粒细胞白血病的生物学功能构建了一个包含638个节点（蛋白质）和1830条边的CML蛋白质 - 蛋白质相互作用网络图，并通过数据库中的网络拓扑性质分析确定了CML分子中的19个关键基因节点。然后，我们使用SYBYL7.3中的Surflex - dock插件进行对接，并从青黛的化学成分与CML网络中的关键蛋白质中获取了参与CML的关键基因的蛋白质晶体结构。
根据评分和空间结构，青黛的药效活性成分是异靛蓝、异靛青、N - 苯基 - 2 - 萘胺和靛红，其中异靛蓝最为重要。我们进一步筛选了CML最有效的活性关键蛋白结构，以便根据最佳对接组合中抑制剂在催化位点的结合相互作用找到青黛的最佳药效活性成分。
结果表明，异靛蓝通过改变PIK3CA、MYC、JAK2和TP53靶蛋白的表达在抵抗CML中发挥作用。网络药理学和分子对接技术可用于寻找中药中可能的活性分子并阐明其分子机制。
BACKGROUND The method of multiple targets overall control is increasingly used to predict the main active ingredient and potential target group of Chinese traditional medicines and to determine the mechanisms involved in their curative effects. Qingdai is the main traditional Chinese medicine used in the treatment of chronic myelogenous leukemia (CML), but the complex active ingredients and antitumor targets in treatment of CML have not been clearly defined in previous studies. MATERIAL AND METHODS We constructed a protein-protein interaction network diagram of CML with 638 nodes (proteins) and 1830 edges, based on the biological function of chronic myelocytic leukemia by use of Cytoscape, and we determined 19 key gene nodes in the CML molecule by network topological properties analysis in a data bank. Then, we used the Surflex-dock plugin in SYBYL7.3 docking and acquired the protein crystal structures of key genes involved in CML from the chemical composition of the traditional Chinese medicine Qingdai with key proteins in CML networks. RESULTS According to the score and the spatial structure, the pharmacodynamically active ingredients of Qingdai are Isdirubin, Isoindigo, N-phenyl-2-naphthylamine, and Isatin, among which Isdirubin is the most important. We further screened the most effective activity key protein structures of CML to find the best pharmacodynamically active ingredients of Qingdai, according to the binding interactions of the inhibitors at the catalytic site performed in best docking combinations. CONCLUSIONS The results suggest that Isdirubin plays a role in resistance to CML by altering the expressions of PIK3CA, MYC, JAK2, and TP53 target proteins. Network pharmacology and molecular docking technology can be used to search for possible reactive molecules in traditional chinese medicines (TCM) and to elucidate their molecular mechanisms.