新型IDO1抑制剂的高通量虚拟筛选，生物验证以及合成探索
发布时间：2018-10-23 12:14
【摘要】：癌症是威胁人类安全健康的最重要的疾病之一。免疫逃避是癌症的特征之一,给癌症的治疗带来了很多困难,所以癌症的免疫治疗成为目前研究的热点。吲哚胺2,3-双加氧酶1(Indoleamine 2,3 dioxygense 1,IDO1)是犬尿氨酸通路的限速酶。犬尿氨酸通路已经被报道和免疫息息相关,IDO1也已经被证明可以可能成为免疫治疗潜在的靶点,有效地抑制IDO1可以帮助杀死癌细胞。除此之外,IDO1还是很多神经性疾病的重要靶点,比如阿尔海默茨病,抑郁症等。目前现有的IDO1抑制剂的数量还保持在一个比较少的数目。可见,IDO1抑制剂的研发具有重要的现实意义。计算机辅助的药物技术在药物的发现,设计及优化中都扮演着重要的角色。其中,计算机辅助的高通量虚拟筛选是快速、高效而且低廉的搜索新型先导化合物的方式。本课题中,为了找到新型IDO1抑制剂,我们采用了一套联合多种方式的全新IDO1虚拟筛选策略,先后采用药效团,虚拟分子对接,ADMET性质的预测和Lipinski五规则多步骤筛选商业数据库ZINC的化合物。通过高通量虚拟筛选方案,我们最后购买了23个全新骨架的化合物,并且进行了体外酶抑制率的测试。其中,有五个化合物在10μM浓度下能达到20%以上的抑制率。抑制率最好的两个化合物做了IC50的测定,值为8.3μM和23.8μM,远远强于常见的抑制剂1-MT(380μM)。最后的生物活性验证了我们的策略是有效的,实用的,同时可以通用于搜索其他的数据库。课题中发现的两个全新骨架化合物会在未来的工作中进行结构改造、优化,有潜力成为IDO1抑制剂的先导化合物。我们最后还探索了hit15的合成路线,设计完成了一条高产率,条件简单的路线,这也为以后的hit15的结构优化奠定了基础。
[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.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914
本文编号：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.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914
【参考文献】
相关期刊论文 前2条
1 夏俊芝;辛建保;白明;;吲哚胺-2,3-双加氧酶在非小细胞肺癌中的表达[J];华中科技大学学报(医学版);2010年01期
2 徐筱杰,陈丽蓉;化学及生物体系中的分子识别[J];化学进展;1996年03期
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