本文關鍵詞：基于系統(tǒng)藥理學的多靶標弱結合藥物發(fā)現(xiàn)方法與應用　出處：《西北農(nóng)林科技大學》2017年博士論文　論文類型：學位論文

  更多相關文章： 系統(tǒng)藥理學 基元模塊 信號通路模擬 分子動力學 多靶標弱結合

【摘要】：藥物-靶標親和力是藥物開發(fā)中的重要指標,傳統(tǒng)藥物設計開發(fā)的中心法則即針對單個靶標設計高選擇性、高親和力的小分子配體,認為靶標越單一、親和力越高,藥效就越好。然而,人們逐漸發(fā)現(xiàn)面對復雜疾病時(例如腫瘤、心血管病、阿爾茲海默病),靶向多個靶標的低親和力藥物比單一靶標的高親和力藥物更優(yōu)秀。近年來網(wǎng)絡藥理學、多向藥理學、系統(tǒng)藥理學等新興學科蓬勃發(fā)展,為多靶標弱結合藥物的開發(fā)奠定了基礎。但是目前仍然缺乏行之有效的多靶標弱結合藥物的發(fā)現(xiàn)方法。為了解決多靶標弱結合藥物發(fā)現(xiàn)中的基本問題,本研究工作基于藥物靶標之間的網(wǎng)絡拓撲結構和動力學參數(shù),以及多靶標弱結合藥物對網(wǎng)絡的擾動特點,提出了一整套藥物發(fā)現(xiàn)新方法,并與藥物發(fā)現(xiàn)實踐相結合,開展了系統(tǒng)性的研究工作。主要發(fā)現(xiàn)如下:(1)提出一種系統(tǒng)動力學方法推理網(wǎng)絡基元模塊,并模擬網(wǎng)絡基元模塊對多點擾動的響應。歸納總結出了33個基元模塊,采用動力學模擬研究了它們在多點擾動下的拓撲結構和動力學參數(shù)變化。結果表明基元模塊的協(xié)同/拮抗效果可以由拓撲結構單獨決定,或者由拓撲結構和動力學參數(shù)共同決定。(2)利用生物范圍合理的參數(shù)集以及常微分方程數(shù)值積分重新構建了濃縮的MAPK信號網(wǎng)絡,并將基元模塊應用于重建的網(wǎng)絡中。重建的系統(tǒng)可以由LPS誘導激活,并且對不同模塊的擾動效果可由IL-6和TNF-α的信號水平來評價。模擬了單靶標強結合藥物以及多靶標弱結合藥物對網(wǎng)絡的擾動情況,從而篩選最優(yōu)靶標組合。結果表明,為了降低MAPK信號通路對炎性刺激的響應水平,設計多靶標弱結合藥物應該優(yōu)先考慮含有p38激酶的靶標組合。(3)以最優(yōu)靶標組合為基礎,采用系統(tǒng)藥理學方法,從中藥系統(tǒng)藥理學數(shù)據(jù)庫中的所有天然產(chǎn)物以及Drugbank數(shù)據(jù)庫中的小分子藥物里反向篩選出32個多靶標化合物,運用分子動力學模擬與結合自由能計算評價了這些化合物的親和力。隨后選取木犀草素與丹參酮IIA作為多靶標弱結合化合物,以幾種激酶抑制劑作為單靶標強結合化合物對照,進行了體外實驗驗證。結果表明,在酶學水平上木犀草素和丹參酮IIA對其靶標的IC50在微摩爾濃度范圍,遠大于現(xiàn)有的激酶抑制劑,但是在細胞抗炎實驗中顯示出與激酶抑制劑相當甚至更好的藥效。綜上所述,本研究系統(tǒng)地分析了網(wǎng)絡基元模塊的性質(zhì)以及如何利用基元模塊選取信號通路中的最優(yōu)靶標組合。同時,基于系統(tǒng)藥理學提出了多靶標弱結合藥物的發(fā)現(xiàn)方法,為新藥開發(fā),老藥新用,天然產(chǎn)物開發(fā)利用提供了新思路。
[Abstract]:Drug target affinity is an important index in drug development. The central rule of traditional drug design and development is to design high selectivity and high affinity small molecule ligands for single target. It is considered that the more single target and the higher affinity, the better the efficacy. However, it has been found that when facing complex diseases, such as tumor, cardiovascular disease, Alzheimer's disease, low affinity drugs targeting multiple targets are better than single target high affinity drugs. In recent years, new disciplines such as network pharmacology, multidirectional pharmacology and systematic pharmacology have developed vigorously, which has laid a foundation for the development of multi targets and weak combination drugs. However, there is still a lack of effective methods for the discovery of multiple targets and weak combination drugs. In order to solve the basic problem of multi target weak combined with drug discovery, this research work based on the drug target between the network topology and the dynamic parameters, and combined with the features of disturbance of multi target weak drugs on the network, puts forward a series of new drug discovery methods, and found that the practice of combining with drugs, carried out the research work of the system. The main findings are as follows: (1) a system dynamics method is proposed to reasoning network primitives and to simulate the response of network primitives to multipoint disturbances. 33 elementary modules are summed up and the dynamics simulation is used to study their topological structure and dynamic parameters. The results show that the synergistic / antagonistic effects of the primitives can be determined solely by the topology or by the topology and dynamic parameters. (2) reconstruct the condensed MAPK signal network by using the reasonable parameter set of biological range and numerical integration of ordinary differential equations, and apply the primitive module to the reconstructed network. The reconstructed system can be activated by LPS, and the disturbance effect on different modules can be evaluated by the signal level of IL-6 and TNF- alpha. The disturbance of the single target strong combination drug and the multi target weak combination drug on the network is simulated, so as to screen the optimal target combination. The results showed that in order to reduce the response level of MAPK signaling pathway to inflammatory stimuli, we should first consider the target combinations containing p38 kinase when designing multi target weak binding drugs. (3) to the optimal target portfolio based system, using pharmacological methods, from small molecule drugs of traditional Chinese medicine pharmacology system database of all natural products as well as in the Drugbank database in reverse screening more than 32 target compounds by molecular dynamics simulation and combining self by the calculation and evaluation of the affinity of these compounds. Subsequently, luteolin and tanshinone IIA were selected as multi target weak binding compounds. Several kinase inhibitors were used as single target strong binding compound control, and were verified in vitro. The results showed that luteolin and tanshinone IIA had higher IC50 concentration in the micromolar range than the existing kinase inhibitors at the enzymology level. But in cell anti-inflammatory experiments, it showed a comparable or even better efficacy than kinase inhibitors. To sum up, this research systematically analyzes the nature of the network primitives module and how to select the optimal target combination in the signal path by using the basic module. At the same time, based on System Pharmacology, the discovery method of multi target weak binding drugs is put forward, which provides a new idea for new drug development, new use of old drugs and natural products development and utilization.
【學位授予單位】：西北農(nóng)林科技大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R96

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