本文選題：整合藥理學(xué) + 銀黃清肺膠囊�。� 參考：《北京中醫(yī)藥大學(xué)》2017年碩士論文

【摘要】：目的:銀黃清肺膠囊是一個含有14味中藥的經(jīng)典名方,其廣泛運(yùn)用于治療慢性支氣管炎并且含有大量的化學(xué)成分。然而,系統(tǒng)研究銀黃清肺膠囊的化學(xué)成分是一個巨大的挑戰(zhàn),目前對該復(fù)方中含有的化學(xué)成分依然不夠清晰。與此同時,雖然銀黃清肺膠囊治療慢性支氣管炎在臨床已取得了良好的效果,但是其藥效基礎(chǔ)和作用機(jī)理仍未明確。為了對銀黃清肺膠囊所含復(fù)雜化學(xué)成分有一個清晰的認(rèn)識,并探索銀黃清肺膠囊治療慢性支氣管炎的作用機(jī)制,運(yùn)用整合藥理學(xué)策略對銀黃清肺膠囊進(jìn)行初步解析,為中藥復(fù)方研究的模式提供新的思路。方法:基于超高效液相色譜串聯(lián)線性離子阱軌道阱質(zhì)譜技術(shù)建立靈敏、高效的分析方法鑒定銀黃清肺膠囊中的化學(xué)成分;運(yùn)用Medchem Studio對銀黃清肺膠囊所含的成分的二維結(jié)構(gòu)與Drugbank數(shù)據(jù)庫中的藥物進(jìn)行靶標(biāo)預(yù)測,并對不同單味藥之間含有的共同靶標(biāo)數(shù)進(jìn)行計算;基于中醫(yī)理論對各單味藥所含靶標(biāo)進(jìn)行功能富集,構(gòu)建"中藥-功效-藥理作用-通路"作用網(wǎng)絡(luò),探索中藥傳統(tǒng)功效與現(xiàn)代藥理作用之間的關(guān)聯(lián);收集與慢性支氣管炎相關(guān)的疾病靶標(biāo)分子,構(gòu)建銀黃清肺膠囊成分靶標(biāo)-疾病靶標(biāo)相互作用網(wǎng)絡(luò),并根據(jù)"連接度"、"節(jié)點(diǎn)介數(shù)"、"緊密度'"、"核心度"四個拓?fù)浣Y(jié)構(gòu)特征值篩選關(guān)鍵節(jié)點(diǎn),并對關(guān)鍵節(jié)點(diǎn)進(jìn)行通路富集分析,構(gòu)建"中藥-靶標(biāo)-通路"作用網(wǎng)絡(luò),找到銀黃清肺膠囊發(fā)揮療效可能參與的生物過程,并明確相應(yīng)關(guān)鍵靶標(biāo)對應(yīng)的化合物。最后用分子對接的手段對分析結(jié)果模擬驗證,通過考察小分子化合物與靶標(biāo)蛋白的結(jié)合能力,間接驗證網(wǎng)絡(luò)藥理學(xué)預(yù)測的可靠性。結(jié)果:1.根據(jù)多級質(zhì)譜數(shù)據(jù),色譜行為,標(biāo)準(zhǔn)品和以前的文獻(xiàn)報道,一共在銀黃清肺膠囊中鑒定了 204個成分,包括黃酮類化合物68個,生物堿類化合物25個,木脂素類化合物22個,有機(jī)酸及其酯類化合物22個,三萜類化合物17個,甾體皂苷類化合物11個,香豆素類化合物11個,萜類化合物6個,檸檬苦素類化合物5個,其他化合物17個。這些化合物的藥材來源也進(jìn)行了分析。其中,37個成分來源于甘草,29個成分來源于銀杏葉,27個成分來源于枳實,24個成分來源于五味子,15個成分來源于枇杷葉,14個成分來源于浙貝母,13個成分來源于新疆一枝蒿,12個成分來源于大青葉,12個成分來源于穿山龍,10個成分來源于蜜麻黃,10個成分來源于苦杏仁,8個成分來源于石菖蒲,6個成分來源于北葶藶子。2.銀黃清肺膠囊成分靶標(biāo)預(yù)測共得到26917個"成分-靶標(biāo)"對,不同單味藥之間含有不同數(shù)目的相同靶標(biāo),提示不同單味藥之間可能具有協(xié)同或拮抗作用,而各單味中藥與銀杏葉之間的共同靶標(biāo)數(shù)均大于其總靶標(biāo)數(shù)的50%,在一定程度上說明銀杏葉與其他各味中藥之間的關(guān)聯(lián)是比較緊密的。3.通過"中藥-功效-藥理作用-通路"相互作用網(wǎng)絡(luò)構(gòu)建,對單味藥成分靶標(biāo)聚集的通路分析,發(fā)現(xiàn)中藥功效與現(xiàn)代藥理活性密切相關(guān)。對銀黃清肺膠囊成分靶標(biāo)-疾病靶標(biāo)相互作用網(wǎng)絡(luò)分析,經(jīng)篩選,共得到475個關(guān)鍵靶標(biāo)。經(jīng)通路富集分析,發(fā)現(xiàn)關(guān)鍵靶標(biāo)顯著富集在炎癥-免疫、支氣管平滑肌收縮和神經(jīng)中樞等功能模塊,而在相關(guān)通路中,多個病理過程均參與到Asthma通路,而聚集到Asthma通路上的IL-3,IL-4,IL-5,IL-10,IL-13,FCER1G,CCL11和EPX這8個分子與慢性支氣管炎的發(fā)病過程密切相關(guān),被認(rèn)為是銀黃清肺膠囊治療慢性支氣管炎過程中所調(diào)控的關(guān)鍵靶標(biāo)分子。分子對接結(jié)果顯示,有17對小分子化合物與靶標(biāo)分子具有強(qiáng)結(jié)合能力。結(jié)論:運(yùn)用液質(zhì)聯(lián)用技術(shù)共鑒別了 204個化合物,為銀黃清肺膠囊進(jìn)一步的質(zhì)量控制研究,藥理活性預(yù)測研究做良好的鋪墊;運(yùn)用網(wǎng)絡(luò)藥理學(xué)技術(shù)進(jìn)行銀黃清肺膠囊靶標(biāo)預(yù)測和網(wǎng)絡(luò)構(gòu)建,在計算水平上闡釋了銀黃清肺膠囊作用于慢性支氣管炎的分子機(jī)制。本文的研究特色及創(chuàng)新點(diǎn):1.基于整合藥理學(xué)策略運(yùn)用超高效液相-高分辨質(zhì)譜聯(lián)用技術(shù)對中藥大復(fù)方銀黃清肺膠囊所含化學(xué)成分進(jìn)行了全面解析,共鑒定了 204個化學(xué)成分;2.基于整合藥理學(xué)策略運(yùn)用網(wǎng)絡(luò)藥理學(xué)預(yù)測技術(shù)對中藥大復(fù)方銀黃清肺膠囊中的關(guān)鍵成分和靶標(biāo)的相互作用關(guān)系進(jìn)行網(wǎng)絡(luò)構(gòu)建,并對關(guān)鍵成分、靶標(biāo)及通路進(jìn)行篩選分析,闡釋銀黃清肺膠囊作用于慢性支氣管炎的分子機(jī)制,并運(yùn)用分子對接技術(shù)進(jìn)行模擬驗證。
[Abstract]:Objective: Yinhuang Qingfei capsule is a classic prescription containing 14 flavors, which is widely used in the treatment of chronic bronchitis and contains a large number of chemical components. However, the chemical composition of Yinhuang Qingfei capsule is a huge challenge, and the chemical composition in the compound is still not clear. At the same time, although the chemical composition of the compound is still not clear. But Yinhuang Qingfei capsule has achieved good results in the treatment of chronic bronchitis, but the basis and mechanism of its efficacy are still not clear. In order to understand the complex chemical components of Yinhuang Qingfei capsule, the mechanism of Yinhuang Qingfei capsule in the treatment of chronic bronchitis is explored, and the integrated pharmacology strategy is used. The preliminary analysis of Yinhuang Qingfei capsule provides a new idea for the model of Chinese medicine compound research. Method: a sensitive and efficient analysis method based on super high performance liquid chromatography tandem linear well track trap mass spectrometry is established to identify the chemical components in Yinhuang Qingfei capsule, and Medchem Studio is used for the formation of Yinhuang Qingfei capsule. The two dimensional structure and the drugs in the Drugbank database are predicted, and the number of common targets among the different single flavors is calculated. Based on the theory of traditional Chinese medicine, the targets are enriched and the "Chinese medicine efficacy pharmacological action pathway" network is constructed to explore the traditional and modern pharmacological effects of traditional Chinese medicine. To collect the target molecules of the disease related to chronic bronchitis, construct the interaction network of Yinhuang Qingfei capsule component target disease target, and select the key nodes according to the "connectivity", "node number", "tightness", "core degree" four topological structure characteristic values, and analyze the key nodes through the path enrichment analysis, and construct "Chinese Medicine -" The target channel "Action Network" is used to find the biological processes that may be involved in the effect of Yinhuang Qingfei capsule, and to clarify the corresponding compounds corresponding to the corresponding key targets. Finally, the analysis results are simulated and verified by the means of molecular docking, and the reliability of the network pharmacology prediction is indirectly verified by investigating the binding ability of the small molecular compound to the target protein. Results: 1. according to multilevel mass spectrometry data, chromatographic behavior, standard products and previous literature reports, a total of 204 components were identified in Yinhuang Qingfei capsule, including 68 flavonoids, 25 alkaloids, 22 lignans, 22 organic acids and their esters, 17 three terpenoids, steroid saponins. There are 11 compounds, 11 coumarins, 6 terpenoids, 5 citrin compounds and 17 other compounds. The sources of these compounds are also analyzed. Among them, 37 components are derived from licorice, 29 are derived from Ginkgo biloba leaves, 27 are derived from Fructus aurantii, 24 components are derived from Schisandra chinensis and 15 sources. In loquat leaf, 14 ingredients come from Fritillaria thunbergii, 13 components come from Artemisia Artemisia in Xinjiang, 12 of them originate from the leaves of dacea, 12 from the Dioscorea, 10 from Ephedra, 10 from bitter almond and 8 from Acorus calamus. 6 components are derived from the target prediction of the.2. Yinhuang Qingfei capsule. A total of 26917 "composition target" pairs were obtained, with different single flavors containing the same target number, suggesting that different single flavors may have synergistic or antagonistic effects. The common target number of each single flavored Chinese medicine and Ginkgo biloba leaves is more than 50% of the total target number. The correlation is a relatively close.3. through the "traditional Chinese medicine efficacy pharmacological action pathway" interaction network construction, the analysis of the pathway of the target aggregation of single flavors, found that the efficacy of traditional Chinese medicine is closely related to the modern pharmacological activity. The analysis of the interaction network of the target target disease target of Yinhuang Qingfei capsule has been screened, and 475 key targets are obtained. By pathway enrichment analysis, it was found that the key targets were significantly enriched in the function modules of inflammatory immunity, bronchial smooth muscle contraction and nerve center, while in the related pathways, multiple pathological processes were involved in the Asthma pathway, and the 8 molecules of IL-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX, on the Asthma pathway, and chronic bronchi The process of inflammation is closely related and is considered to be the key target molecule controlled by Yinhuang Qingfei capsule in the treatment of chronic bronchitis. Molecular docking results show that there are 17 pairs of small molecules with strong binding ability to the target molecule. Conclusion: 204 compounds were identified by the technique of liquid chromatography-using yellowish yellow Qingfei capsule. One step of quality control research, pharmacological activity prediction research to make good paving, using network pharmacology to predict the target and network construction of Yinhuang Qingfei capsule, explain the molecular mechanism of Yinhuang Qingfei capsule acting on chronic bronchitis. The characteristics and innovation of this paper: 1. based on integrated pharmacology policy The chemical components of the big compound Yinhuang Qingfei capsule were comprehensively analyzed by super high performance liquid phase high resolution mass spectrometry, and 204 chemical components were identified. 2. based on the integrated pharmacology strategy, the interaction between the key components and target in the big compound silver Huang Qingfei capsule was made by using the network pharmacology prediction technology. The key components, targets and pathways were screened and analyzed by using the relationship. The molecular mechanism of Yinhuang Qingfei Capsule on chronic bronchitis was explained, and the molecular docking technique was used to simulate and verify the molecular mechanism.
【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R286.0;R285

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