Analysis of the Pharmacodynamic Material Basis and Mechanism of Dendrobium Nobile in the Treatment of Nervous System Diseases Using Integrative Network Pharmacology
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摘要: 目的：基于网络药理学分析金钗石斛治疗神经系统疾病的药效物质基础及作用机制。方法：检索Si-noMed、中国知网、万方等数据库获取金钗石斛中的化学成分，将成分录入TargetNet数据库以获取潜在靶点，再将靶点导入CTD数据库检索相关疾病，导入DAVID数据库获取靶点的基因功能及作用通路。用Cytoscape软件构建“成分-靶点”及“靶点-疾病”网络等进一步可视化整合分析。并采用AutoDock Vina软件对关键成分与靶点进行分子对接验证。结果：本研究共收集到金钗石斛中47个成分，可作用于88个靶点，进一步分析可知Nobilin D、Nobliomethylene、decumbic acid B、（+）-dendrolactone、（−）-denobilone A和Nobilin等成分是金钗石斛治疗神经系统疾病的主要药效物质基础，可作用于MIF、ERS2、CYP19A1、ABCG2、TLR9和DRD5等关键靶点，通过调节Sphingolipid signaling pathway、Cocaine addiction及Serotonergic synapse等信号通路来发挥治疗神经系统疾病的作用。结论：本研究揭示了金钗石斛多成分、多靶点、多途径的作用规律，为深入开展金钗石斛治疗神经系统疾病的作用机制研究提供新的依据。Abstract: Objective: To analyze the pharmacodynamic material basis and mechanism of Dendrobium nobile in the treatment of nervous system diseases using integrative network pharmacology. Methods: The chemical constituents of Dendrobium nobile were collected from the databases of Si-noMed, China HowNet and Wanfang. The constituents were input into TargetNet database for potential target capture. The obtained target was then imported into CTD database to get related diseases. The gene function and pathway enrichment of the target were analyzed by DAVID database. Component-target network and target-disease network were constructed by Cytoscape software. The relation between the ingredients and targets were validated by AutoDock Vina software. Results: A total of 47 components were collected from Dendrobium nobile, which could act on 88 targets. Nobilin D, Nobliomethylene, decumbic acid B, (+)-dendrolactone, (−)-denobilone A, Nobilin were the main material basis for the treatment of nervous system diseases through multivariate network analysis. The components in Dendrobium nobile mainly acted on these key targets including MIF, ERS2, CYP19A1, ABCG2, TLR9 and DRD5, and further regulate the Sphingolipid signaling pathway, Cocaine addiction and Serotonergic synapse for treating nervous system diseases. Conclusion: This study reveals the multi-component, multi-target and multi-pathway action of Dendrobium nobile, and provides a new basis for further research on the mechanism of Dendrobium nobile in the treatment of nervous system diseases.
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Key words:
- Dendrobium nobile /
- nervous system diseases /
- network pharmacology /
- mechanism
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图 5 前20个KEGG通路富集气泡图（P<0.05）
Figure 5. Enrichment bubble diagram of the first 20 KEGG pathways (P<0.05)
图 6 ESR2、MIF、ABCG2、CYP19A1与化合物结合能最低的最佳对接构象
Figure 6. The best docking conformation of ESR2, MIF, ABCG2, CYP19A1 and the compounds with the lowest binding energy
注：A.ESR2与化合物C25的最佳对接构象；B. MIF与化合物C42最佳对接构象；C. ABCG2与化合物C25的最佳对接构象；D.CYP19A1与化合物C32的最佳对接构象。
表 1 金钗石斛中的化学成分信息
Table 1. Chemical constituents of Dendrobium nobile
编号 化合物名称 化合物中文名 度 编号 化合物名称 化合物中文名 度 C1 Moscatilin 杓唇石斛素 22 C25 Dendrobine 石斛碱 29 C2 Gigantol 石斛酚 24 C26 Noblilonine 野百合碱 18 C3 Nobilin A 果香菊素A 8 C27 10,12-dihydroxypicrotoxane 10,12-二羟基吡咯烷 21 C4 Nobilin E 果香菊素E 10 C28 Mubironines B 21 C5 Denbinobin 石斛醌 23 C29 Mubironines C 12 C6 2,2'-dihydroxy-3,3',4,4',7,7'-hexamethoxy-9,9',
10,10'-tetrahydroxy-1,1'-biphenanthrene27 C30 Dendronobiline A 0 C7 2,5-dihydroxy-4,9-dimethoxyphenanthrene 2,5-二羟基-4,9-二甲氧基菲 29 C31 Nobilin D 果香菊素 D 42 C8 Confusarin 毛兰菲 26 C32 Nobilin 果香菊素 30 C9 1R,2R,4S,5S,6S,8S,9R,-2，
8-dihydroxycopacamphan-15-one1R，2R，4S，5S，6S，8S，9R，-2,
8-二羟基乙酰氨基甲酸-15-酮15 C33 Nobilone 贵石斛碱 29 C10 2β,3β,4β,5β-2,4,
11-trihydroxypicrotoxano-3(15)-lactone4 C34 4,α-dihydroxy-3,5,
3'-trimethoxybibenzyl4，α-二羟基-3,5,
3'-三甲氧基联苄19 C11 2β,3β,5β,9α,11β-2,11-epoxy-9,11,
13-trihydroxypicrotoxano-3(15)-lactone9 C35 4,5-dihydroxy-3',
3-dimethoxybibenzyl4,5-二羟基-3'，
3-二甲氧基联苄27 C12 2β,3β,5β,12R*-2，11，
13-trihydroxypicrotoxano-3(15)-lactone10 C36 Decumbic acid A 癸二酸A 26 C13 2β,3β,5β,12S*-2，11，
13-trihydroxypicrotoxano-3(15)-lactone10 C37 Decumbic acid B 癸二酸B 33 C14 2β,3β,5β,9α-9，1O-cyclo-2,11，
13-trihydroxypicrotoxano-3(15)-lactone17 C38 (−)-decumbic acid (−)-癸二酸 26 C15 9β,10α-muurol-4-ene-9,10,11-triol 13 C39 (−)-dendrolactone （−）-树内酯 29 C16 10α-alloaromadendrane-10,12,14-triol 13 C40 (+)-dendrolactone （+）-树内酯 32 C17 5β-cyclocopacaphane-5,12,15-triol 7 C41 (+)-denobilone A （+）-二苯酮A 26 C18 δ-cadinen-12,14-diol δ-杜松萜烯-12,14-二醇 10 C42 (−)-denobilone A （−）-二苯酮A 30 C19 Nobliomethylene 38 C43 Dendroside 石斛苷 27 C20 Flakinin A 8 C44 Syringarresinol 24 C21 Dendronobiloside A 石斛苷A 8 C45 Pionresinol 松脂醇 28 C22 Dendronobilin A 金钗石斛素A 13 C46 Medioresinol 皮树脂醇 27 C23 Dendrodensiflorol 石斛醇 20 C47 Lirioresinol-A 鹅掌楸树脂醇A 0 C24 Dendronobilin K 金钗石斛素K 29 
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表 2 金钗石斛前20个潜在作用靶点疾病名称及疾病分类
Table 2. Disease names and disease classification of the first 20 potential targets of Dendrobium nobile
疾病名称 疾病分类 疾病ID 癫痫 神经系统疾病 MESH:D004827 低血压 心血管疾病|神经系统疾病 MESH:D007024 滥用大麻 精神障碍|物质相关障碍 MESH:D002189 精神障碍 精神障碍 MESH:D001523 神经系统疾病 神经系统疾病 MESH:D009422 神经中毒综合征 神经系统疾病 MESH:D020258 帕金森病 神经系统疾病 MESH:D010300 继发性帕金森病 神经系统疾病 MESH:D010302 周围神经系统疾病 神经系统疾病 MESH:D010523 神经系统疾病 神经系统疾病 MESH:D009422 阿尔茨海默病 精神障碍|物质相关障碍 MESH:D000544 苯丙胺相关疾病 精神障碍|神经系统疾病 MESH:D019969 学习障碍 精神障碍|神经系统疾病|体征和症状 MESH:D007859 记忆障碍 神经系统疾病|体征和症状 MESH:D008569 运动障碍疾病 神经系统疾病 MESH:D009069 神经系统疾病 神经系统疾病 MESH:D009422 癫痫发作 神经系统疾病|体征和症状 MESH:D012640 震颤 神经系统疾病|体征和症状 MESH:D014202 神经中毒综合征 神经系统疾病 MESH:D020258 癫痫发作 神经系统疾病|体征和症状 MESH:D012640
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表 3 金钗石斛治疗神经系统疾病靶点的生物进程分析结果
Table 3. Biological process analysis results of Dendrobium nobile in the treatment of nervous system diseases
GO生物过程 基因数 相关基因百分比(％) P 细胞对药物的反应 22 4.55 0 痛觉 9 6.67 0 对雌二醇的反应 8 4.68 0 肽基苏氨酸磷酸化 7 4.17 0 阿片受体信号通路 3 25 0 慢性炎症反应 3 12.5 0 食欲调节 3 10.34 0 类固醇分解代谢过程 3 9.38 0 细胞对镉离子的反应 3 8.11 0 负离子转运的正调控 3 4.41 0
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表 4 金钗石斛作用的4个靶点与11个成分的分子对接得分
Table 4. Molecular docking scores of 4 targets and 11 components of Dendrobium nobile
靶点蛋白 靶点蛋白ID 化合物 结合能（kCal/mol） 均方根偏差 ESR2 2qtu C7 −10.1 1.061 C19 −10.2 0.678 C24 −9.9 0.817 C25 −11.1 0.649 C31 −8.2 1.104 C32 −10.3 1.327 C33 −8.9 1.419 C37 −6.7 1.269 C39 −8.6 0.027 C40 −10.5 0.735 C42 −10.5 1.547 MIF 5xej C7 −8.9 1.082 C19 −9.3 1.590 C24 −9.4 1.422 C25 −9.2 1.427 C31 −8.3 1.784 C32 −9.7 1.083 C33 −8.3 0.799 C37 −6.2 1.842 C39 −7.5 0.051 C40 −10.0 1.017 C42 −10.0 1.010 ABCG2 6ffc C7 −10.6 1.836 C19 −11.3 1.108 C24 −9.8 1.096 C25 −11.5 0.861 C31 −8.3 1.078 C32 −11.2 1.217 C33 −9.6 1.031 C37 −6.6 1.135 C39 −8.0 0.035 C40 −10.5 1.272 C42 −10.5 1.416 CYP19A1 5jl6 C7 −8.4 1.182 C19 −8.5 1.351 C24 − − C25 −8.9 1.766 C31 −8.0 0.063 C32 −9.0 1.189 C33 −7.9 0.660 C37 −6.6 1.036 C39 −7.4 0.019 C40 −8.7 1.048 C42 −8.7 1.043
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