新型IDO1抑制劑的高通量虛擬篩選，生物驗(yàn)證以及合成探索
發(fā)布時(shí)間：2018-10-23 12:14
【摘要】：癌癥是威脅人類安全健康的最重要的疾病之一。免疫逃避是癌癥的特征之一,給癌癥的治療帶來了很多困難,所以癌癥的免疫治療成為目前研究的熱點(diǎn)。吲哚胺2,3-雙加氧酶1(Indoleamine 2,3 dioxygense 1,IDO1)是犬尿氨酸通路的限速酶。犬尿氨酸通路已經(jīng)被報(bào)道和免疫息息相關(guān),IDO1也已經(jīng)被證明可以可能成為免疫治療潛在的靶點(diǎn),有效地抑制IDO1可以幫助殺死癌細(xì)胞。除此之外,IDO1還是很多神經(jīng)性疾病的重要靶點(diǎn),比如阿爾海默茨病,抑郁癥等。目前現(xiàn)有的IDO1抑制劑的數(shù)量還保持在一個(gè)比較少的數(shù)目�？梢�,IDO1抑制劑的研發(fā)具有重要的現(xiàn)實(shí)意義。計(jì)算機(jī)輔助的藥物技術(shù)在藥物的發(fā)現(xiàn),設(shè)計(jì)及優(yōu)化中都扮演著重要的角色。其中,計(jì)算機(jī)輔助的高通量虛擬篩選是快速、高效而且低廉的搜索新型先導(dǎo)化合物的方式。本課題中,為了找到新型IDO1抑制劑,我們采用了一套聯(lián)合多種方式的全新IDO1虛擬篩選策略,先后采用藥效團(tuán),虛擬分子對(duì)接,ADMET性質(zhì)的預(yù)測(cè)和Lipinski五規(guī)則多步驟篩選商業(yè)數(shù)據(jù)庫ZINC的化合物。通過高通量虛擬篩選方案,我們最后購買了23個(gè)全新骨架的化合物,并且進(jìn)行了體外酶抑制率的測(cè)試。其中,有五個(gè)化合物在10μM濃度下能達(dá)到20%以上的抑制率。抑制率最好的兩個(gè)化合物做了IC50的測(cè)定,值為8.3μM和23.8μM,遠(yuǎn)遠(yuǎn)強(qiáng)于常見的抑制劑1-MT(380μM)。最后的生物活性驗(yàn)證了我們的策略是有效的,實(shí)用的,同時(shí)可以通用于搜索其他的數(shù)據(jù)庫。課題中發(fā)現(xiàn)的兩個(gè)全新骨架化合物會(huì)在未來的工作中進(jìn)行結(jié)構(gòu)改造、優(yōu)化,有潛力成為IDO1抑制劑的先導(dǎo)化合物。我們最后還探索了hit15的合成路線,設(shè)計(jì)完成了一條高產(chǎn)率,條件簡(jiǎn)單的路線,這也為以后的hit15的結(jié)構(gòu)優(yōu)化奠定了基礎(chǔ)。
[Abstract]:Cancer is one of the most important diseases threatening the safety and health of human beings. Immune evasion is one of the characteristics of cancer, which brings a lot of difficulties to the treatment of cancer. Indoleamine (Indoleamine _ 2N _ 3-dioxygenase _ 1) is a rate-limiting enzyme in the canine uric acid pathway. The canine uric acid pathway has been reported to be closely related to immune response, and IDO1 has been shown to be a potential target for immunotherapy, and the suppression of IDO1 can help kill cancer cells. In addition, IDO1 is also an important target for many neurological diseases, such as Alzheimer's disease, depression and so on. The current number of IDO1 inhibitors remains at a relatively small number. Thus, the development of IDO1 inhibitors has important practical significance. Computer-aided drug technology plays an important role in drug discovery, design and optimization. Computer-assisted high-throughput virtual screening is a fast, efficient and inexpensive way to search for new lead compounds. In this study, in order to find new IDO1 inhibitors, we adopted a new IDO1 virtual screening strategy combined with many ways, and used pharmacophore successively. Virtual molecular docking, ADMET properties prediction and Lipinski five-rule multistep screening of commercial database ZINC compounds. Through a high-throughput virtual screening scheme, we finally purchased 23 new cytoskeleton compounds and tested the inhibition rate of enzymes in vitro. Among them, five compounds could achieve more than 20% inhibition rate at 10 渭 M concentration. The two compounds with the best inhibition rates were tested for IC50, at 8.3 渭 M and 23.8 渭 M, which is much stronger than the common inhibitor 1-MT (380 渭 M). The final bioactivity verifies that our strategy is effective, practical, and can be used to search other databases. The two new skeleton compounds found in this paper will be modified and optimized in the future, and have the potential to be the leading compounds of IDO1 inhibitors. Finally, we explored the synthetic route of hit15, designed a route with high yield and simple conditions, which laid a foundation for the structural optimization of hit15 in the future.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
本文編號(hào)：2289203
[Abstract]:Cancer is one of the most important diseases threatening the safety and health of human beings. Immune evasion is one of the characteristics of cancer, which brings a lot of difficulties to the treatment of cancer. Indoleamine (Indoleamine _ 2N _ 3-dioxygenase _ 1) is a rate-limiting enzyme in the canine uric acid pathway. The canine uric acid pathway has been reported to be closely related to immune response, and IDO1 has been shown to be a potential target for immunotherapy, and the suppression of IDO1 can help kill cancer cells. In addition, IDO1 is also an important target for many neurological diseases, such as Alzheimer's disease, depression and so on. The current number of IDO1 inhibitors remains at a relatively small number. Thus, the development of IDO1 inhibitors has important practical significance. Computer-aided drug technology plays an important role in drug discovery, design and optimization. Computer-assisted high-throughput virtual screening is a fast, efficient and inexpensive way to search for new lead compounds. In this study, in order to find new IDO1 inhibitors, we adopted a new IDO1 virtual screening strategy combined with many ways, and used pharmacophore successively. Virtual molecular docking, ADMET properties prediction and Lipinski five-rule multistep screening of commercial database ZINC compounds. Through a high-throughput virtual screening scheme, we finally purchased 23 new cytoskeleton compounds and tested the inhibition rate of enzymes in vitro. Among them, five compounds could achieve more than 20% inhibition rate at 10 渭 M concentration. The two compounds with the best inhibition rates were tested for IC50, at 8.3 渭 M and 23.8 渭 M, which is much stronger than the common inhibitor 1-MT (380 渭 M). The final bioactivity verifies that our strategy is effective, practical, and can be used to search other databases. The two new skeleton compounds found in this paper will be modified and optimized in the future, and have the potential to be the leading compounds of IDO1 inhibitors. Finally, we explored the synthetic route of hit15, designed a route with high yield and simple conditions, which laid a foundation for the structural optimization of hit15 in the future.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
1 夏俊芝;辛建保;白明;;吲哚胺-2,3-雙加氧酶在非小細(xì)胞肺癌中的表達(dá)[J];華中科技大學(xué)學(xué)報(bào)(醫(yī)學(xué)版);2010年01期
2 徐筱杰,陳麗蓉;化學(xué)及生物體系中的分子識(shí)別[J];化學(xué)進(jìn)展;1996年03期
，本文編號(hào)：2289203
本文鏈接：http://sikaile.net/yixuelunwen/yiyaoxuelunwen/2289203.html
最近更新
教材專著
