本文選題：化學(xué)信息學(xué) + 心衰　； 參考：《第二軍醫(yī)大學(xué)》2017年博士論文

【摘要】：心衰是一種常見(jiàn)的、昂貴的、可能致命的疾病,近年來(lái),心衰的患病率和發(fā)病率正在逐年增加,心衰疾病已經(jīng)發(fā)展成為一個(gè)常見(jiàn)的公共問(wèn)題。本論文采用化學(xué)信息學(xué)手段虛擬篩選靶向心衰潛在靶標(biāo)蛋白腫瘤壞死因子-α的小分子拮抗劑,并進(jìn)行實(shí)驗(yàn)驗(yàn)證。同時(shí),將化學(xué)信息學(xué)工具與網(wǎng)絡(luò)藥理學(xué)理念相整合,探討四逆湯抗心衰的潛在作用機(jī)制,并構(gòu)建了一個(gè)心衰相關(guān)中草藥網(wǎng)絡(luò)藥理平臺(tái),為抗心衰中藥復(fù)方、藥材和化合物的靶標(biāo)鑒定及網(wǎng)絡(luò)藥理機(jī)制探討提供了一個(gè)專(zhuān)有的網(wǎng)絡(luò)平臺(tái)。1.基于虛擬篩選的腫瘤壞死因子-α小分子拮抗劑的預(yù)測(cè)和驗(yàn)證腫瘤壞死因子-α是治療心衰疾病的潛在靶標(biāo)蛋白,然而,目前報(bào)道的腫瘤壞死因子-α小分子抑制劑數(shù)量非常有限。本研究擬將虛擬篩選與生物驗(yàn)證相結(jié)合,快速高效地篩選與腫瘤壞死因子-α相結(jié)合的拮抗劑。首先,采用藥效團(tuán)模型和分子對(duì)接方法虛擬篩選specs商業(yè)庫(kù),然后,將得到的目標(biāo)化合物進(jìn)行表面等離子共振分析,得到4個(gè)不同骨架的腫瘤壞死因子-α結(jié)合配體。其中,T1與腫瘤壞死因子-α的親和力最強(qiáng)(Kd=11μM),該親和值與已有的腫瘤壞死因子-α小分子拮抗劑活性相當(dāng)。進(jìn)一步的細(xì)胞實(shí)驗(yàn)結(jié)果也表明T1與已知拮抗劑C87的活性相近。本研究不僅提供了一些腫瘤壞死因子-α小分子拮抗劑的新骨架,用于進(jìn)一步的結(jié)構(gòu)優(yōu)化,同時(shí)也證明了虛擬篩選策略在腫瘤壞死因子-α小分子拮抗劑鑒別方面的實(shí)用性。2.基于代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)相結(jié)合的四逆湯抗阿霉素誘導(dǎo)心衰作用研究四逆湯是一味經(jīng)典的治療阿霉素誘導(dǎo)心衰的中藥復(fù)方,由附子、干姜和甘草組成。目前的化學(xué)物質(zhì)組學(xué)和藥理學(xué)研究表明四逆湯主要的活性部位為附子總生物堿、干姜總姜酚、甘草總黃酮以及甘草總皂苷。本研究的動(dòng)物實(shí)驗(yàn)結(jié)果表明四逆湯有效部位配伍治療效果與四逆湯相近,比兩兩配伍或單組分配伍的療效好。盡管四逆湯有效部位配伍的療效明確,但是由于其成分的復(fù)雜性,其作用機(jī)制仍不明確。本研究旨在首次聯(lián)用代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)方法探討四逆湯有效部位配伍治療心衰的潛在作用機(jī)制。通過(guò)基于GC/LC-MS的整體代謝組學(xué)策略,我們發(fā)現(xiàn)四逆湯有效部位配伍主要通過(guò)調(diào)控6個(gè)代謝通路發(fā)揮療效。然后,我們進(jìn)行了網(wǎng)絡(luò)藥理學(xué)研究,通過(guò)分子對(duì)接技術(shù)找到了有效部位作用的17個(gè)心血管疾病相關(guān)的潛在靶點(diǎn),其中11個(gè)被文獻(xiàn)證明為有效部位中化學(xué)成分的靶點(diǎn),該結(jié)果也從網(wǎng)絡(luò)藥理學(xué)的角度證明了四逆湯有效部位整體的治療效果。在找到的17個(gè)潛在靶標(biāo)中,磷酸肌醇3-激酶γ、胰島素受體、鳥(niǎo)氨酸轉(zhuǎn)氨酶和葡糖激酶存在于四逆湯有效部位所調(diào)控的代謝通路中。并且,磷酸肌醇3-激酶γ、胰島素受體和葡糖激酶已經(jīng)被文獻(xiàn)證明為四逆湯有效部位中化學(xué)成分的靶標(biāo)。我們的研究也表明附子總生物堿是主要的活性成分,干姜總姜酚和甘草總黃酮總皂苷是輔助成分。代謝組學(xué)和網(wǎng)絡(luò)藥理學(xué)的聯(lián)用為更全面可靠地挖掘中藥化學(xué)物質(zhì)組所作用的靶標(biāo)群提供了可能,并為傳統(tǒng)中藥復(fù)方治療作用的探討提供了新的思路。3.基于網(wǎng)絡(luò)分析的四逆湯活性成分的靶標(biāo)鑒別及機(jī)制研究同步鑒別化學(xué)物質(zhì)組的靶標(biāo)群是當(dāng)前面臨的一個(gè)重要的且尚未解決的難題。在本研究中,我們創(chuàng)新性地整合了網(wǎng)絡(luò)藥理學(xué)和代謝組學(xué)數(shù)據(jù),首次提出了網(wǎng)絡(luò)分析的方法,用于同步鑒別四逆湯中抗心衰活性物質(zhì)組的潛在靶標(biāo)群。首先,我們通過(guò)血清藥物化學(xué)、文本挖掘和相似性匹配相結(jié)合的方法鑒別出四逆湯抗心衰的48個(gè)潛在活性成分。然后采用文本挖掘和分子對(duì)接的方法鑒別這些活性成分的潛在靶標(biāo),并通過(guò)STRING數(shù)據(jù)庫(kù)對(duì)這些靶標(biāo)蛋白相關(guān)的生物過(guò)程,通路和相關(guān)疾病進(jìn)行了富集分析。最后,整合代謝組學(xué)數(shù)據(jù)進(jìn)行網(wǎng)絡(luò)分析進(jìn)一步篩選四逆湯活性成分的靶標(biāo)蛋白,以提高文本挖掘和分子對(duì)接方法的準(zhǔn)確性。在網(wǎng)絡(luò)分析鑒別出的25個(gè)潛在靶標(biāo)蛋白中,腫瘤壞死因子-α被首次驗(yàn)證為四逆湯中次烏頭堿、新烏頭堿、去甲烏藥堿和槲皮素的靶標(biāo)。表面等離子共振實(shí)驗(yàn)表明這些化合物能與腫瘤壞死因子-α直接結(jié)合。細(xì)胞實(shí)驗(yàn)結(jié)果也表明這些化合物能緩解腫瘤壞死因子-α導(dǎo)致的L929細(xì)胞毒性,并抑制阿霉素誘導(dǎo)的H9C2心肌細(xì)胞凋亡。我們期望網(wǎng)絡(luò)分析也能被用于活性單體靶標(biāo)的鑒別。4.HF-Net Pharm:心衰相關(guān)中草藥網(wǎng)絡(luò)藥理平臺(tái)的構(gòu)建幾千年來(lái),作為多靶標(biāo)療法的代表,中藥復(fù)方已經(jīng)被成功地用于治療多種疾病。然而,研究方法的缺乏極大地限制了其作用機(jī)制的探討。本章首次構(gòu)建了一個(gè)心衰相關(guān)中草藥網(wǎng)絡(luò)藥理平臺(tái)(HF-Net Pharm,www.cbligand.org/HF),用于中藥復(fù)方作用機(jī)制的研究。該平臺(tái)搜集了46個(gè)治療心衰的中藥復(fù)方、復(fù)方中111種藥材以及藥材中13,301個(gè)化合物的信息。同時(shí),還整合了所有文獻(xiàn)報(bào)道的心衰相關(guān)化學(xué)基因組學(xué)數(shù)據(jù),包括259個(gè)心衰相關(guān)的靶標(biāo)蛋白和77個(gè)治療心衰的上市或臨床試驗(yàn)藥。為了對(duì)化合物的靶標(biāo)進(jìn)行預(yù)測(cè),我們嵌入了Target Hunter和HTDocking模塊。并且還對(duì)心衰相關(guān)網(wǎng)絡(luò)藥理平臺(tái)的應(yīng)用進(jìn)行了舉例,包括活性化合物的靶標(biāo)鑒別,FDA批準(zhǔn)抗心衰藥物和草藥抗心衰活性成分的多向藥理分析,以及抗心衰中藥復(fù)方的網(wǎng)絡(luò)藥理研究。通過(guò)文本挖掘和體外實(shí)驗(yàn)對(duì)預(yù)測(cè)結(jié)果進(jìn)行了驗(yàn)證。本研究構(gòu)建的心衰相關(guān)中草藥網(wǎng)絡(luò)藥理平臺(tái)將有助于中藥材來(lái)源的藥物發(fā)現(xiàn)、心衰相關(guān)的靶標(biāo)鑒別、多向藥理研究及中藥復(fù)方的網(wǎng)絡(luò)藥理學(xué)研究。
[Abstract]:Heart failure is a common, expensive, and potentially fatal disease. In recent years, the prevalence and incidence of heart failure are increasing year by year. Heart failure disease has developed into a common public problem. This paper uses chemical informatics to virtual screening of small molecular antagonists targeting the target protein TNF - alpha targeting target protein, tumor necrosis factor - alpha. At the same time, the chemical informatics tool and the concept of network pharmacology are integrated to explore the potential mechanism of the anti heart failure of the four reverse soup, and a network pharmacology platform of the Chinese herbal medicine for heart failure is constructed, which provides a proprietary for the target identification of anti heart failure, the target identification of medicinal materials and compounds and the study of the network pharmacological mechanism. The network platform.1. predicts and verifies that TNF - alpha is a potential target protein for the treatment of heart failure based on the virtual screening of tumor necrosis factor - alpha small molecule antagonists. However, the number of small molecular inhibitors of TNF - alpha is very limited. Screening the antagonists with tumor necrosis factor alpha (TNF - alpha). First, the pharmacophore model and molecular docking method were used to selectively screen the specs commercial bank. Then, the target compounds were analyzed by surface plasmon resonance, and 4 tumor necrosis factor alpha binding ligands were obtained with different skeletons. Among them, T1 and tumor necrosis factor - alpha The affinity is the strongest (Kd=11 mu M), which is equivalent to the existing tumor necrosis factor - alpha small molecule antagonist. Further cell test results also show that the activity of T1 is similar to that of the known antagonist C87. This study not only provided some new skeleton of tumor necrosis factor - alpha small molecule antagonist, but also used for further structural optimization. The practicability of the virtual screening strategy in the identification of TNF - alpha small molecule antagonists.2. based on the combination of metabonomics and network pharmacology four inverse soup against adriamycin induced heart failure four reverse decoction is a classic Chinese herbal compound for the treatment of adriamycin induced heart failure, consisting of Aconitum, dried ginger and Glycyrrhiza. The previous study of chemical composition and pharmacology showed that the main active sites of the four reverse soup were total alkaloids of aconite, total ginger, total flavonoids and total liquorice saponins. The results of this study showed that the effective part of the four reverse soup was similar to the four reverse soup, and the effect was better than the compatibility of the 22 or the single component. The efficacy of the effective parts of the four reverse soup is clear, but its mechanism is still not clear due to the complexity of its components. The purpose of this study is to explore the potential mechanism of the effective part of the four reverse soup in the treatment of heart failure for the first time by means of metabonomics and network pharmacology. Through the overall metabolic strategy based on GC/ LC-MS, we found four The efficacy of the effective parts of the decoction is mainly controlled by the regulation of the 6 metabolic pathways. Then, we have conducted a network pharmacology study to find the potential targets of 17 cardiovascular diseases related to the effective parts of the site by molecular docking technique, and 11 of them were proved to be the targets of the chemical components in the effective part, and the results were also from the network. Pharmacologic points of view demonstrate the overall therapeutic effect of the effective parts of the four reverse soup. Among the 17 potential targets found, the inositol 3- kinase gamma, the insulin receptor, ornithine aminotransferase and glucokinase exist in the metabolic pathways regulated by the effective parts of the four reverse soup. And, the inositol phosphoric acid 3- kinase gamma, insulin receptor and glucokinase have already been found. Our study also showed that the total alkaloid of aconite is the main active ingredient, the total saponins of total ginger and total flavonoids of dried ginger are auxiliary components. The combination of metabolomics and network pharmacology is a more comprehensive and reliable target group for digging the chemical substance group of Chinese medicine more fully and reliably. It provides the possibility, and provides a new idea for the discussion of the therapeutic effect of traditional Chinese medicine compound. The target identification and mechanism of the active ingredient of the four inverse soup based on network analysis is an important and unsolved problem that the target group is facing at present. In this study, we have innovatively integrated it in this study. Network pharmacology and metabonomics data for the first time proposed a network analysis method for the simultaneous identification of the potential target groups of anti heart failure active substances in the four reverse soup. First, we identified the 48 potential active components of the anti heart failure of the four reverse soup through the combination of serum drug chemistry, text mining and similarity matching. Text mining and molecular docking methods identify the potential targets of these active components, and enrich the biological processes, pathways and related diseases related to these target proteins through the STRING database. Finally, the integrated metabolic data is integrated to screen the target proteins of the active ingredients of the four reverse soup to improve the text. The accuracy of this method of mining and molecular docking. In the 25 potential target proteins identified by network analysis, TNF - alpha was first verified as the target of aconitine, neoaconitine, noracinine and quercetin in four reverse soup. Surface plasmon resonance experiments showed that these compounds could be directly combined with tumor necrosis factor - alpha. The results of cell experiments also indicate that these compounds can alleviate the toxicity of tumor necrosis factor - alpha induced L929 cells and inhibit the apoptosis of H9C2 induced cardiomyocytes induced by adriamycin. We expect that network analysis can also be used for the identification of.4.HF-Net Pharm: heart failure related Chinese herbal medicine platform for thousands of years. The traditional Chinese medicine compound has been successfully used in the treatment of various diseases. However, the lack of research methods greatly restricts the discussion of its mechanism of action. In this chapter, a HF-Net Pharm (www.cbligand.org /HF) was first constructed for the study of the mechanism of the action of Chinese herbal compound. 46 compound Chinese medicine for the treatment of heart failure, 111 kinds of medicinal materials in the compound, and information of 13301 compounds in the medicinal materials were collected. At the same time, all the reports of heart failure related chemical genomics data, including 259 heart failure related target proteins and 77 listed or clinical trial drugs for the treatment of heart failure, were integrated. We embed the Target Hunter and HTDocking modules. We also exemplify the application of the pharmacological platform of the heart failure related network, including the target identification of active compounds, the multidirectional pharmacological analysis of the anti heart failure drugs and the anti heart failure active components of the herbal medicine by FDA, and the network pharmacology of the Chinese herbal compound of anti heart failure. The prediction results were verified by text mining and in vitro experiments. The network pharmacology platform of heart failure related herbal medicine constructed in this study will be helpful to the drug discovery of Chinese medicinal materials, the target identification of heart failure related, multi direction pharmacological research and the network pharmacology research of Chinese medicine compound.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R285

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