吲哚胺2,3-双加氧酶的小分子抑制剂的药物发现和机理研究

发布时间：2018-04-12 19:41

本文选题：IDO1 + 虚拟筛选　；参考：《青岛大学》2017年硕士论文

【摘要】：吲哚胺2,3双加氧酶1(Indolemine 2,3-dioxygenase,IDO1)是包含亚铁血红素的细胞内单体酶,位于两个结构域域中的亚铁血红素负责催化L-色氨酸通过犬尿氨酸降解途径的初始和速率限制步骤。这个反应通过色氨酸吲哚环的氧化反应发生,分别由IDO1、IDO2和TDO在哺乳类动物中单独催化。该催化反应导致一系列生物活性物的代谢产物,包含神经递质5-羟色胺、喹啉酸、褪黑素、N-甲基-D-天冬氨酸受体拮抗剂、犬尿酸及烟酰胺腺嘌呤二核苷酸的最终产物。T细胞对于色氨酸的降解和色氨酸代谢物的积累非常敏感,而IDO1通过分解代谢色氨酸,进而抑制T细胞的增殖和分化。事实上,已经发现IDO1在很多人类癌细胞中可以直接发挥防止T细胞攻击的作用而在细胞中过度表达,例如乳腺癌,前列腺癌,肺癌和直肠癌。此外,发现IDO1在抗原呈递细胞中表达,在肿瘤引流淋巴结中发挥着对于肿瘤相关抗原加强外围容忍的作用。通过这些机制,IDO1促进恶性肿瘤细胞表达肿瘤相关抗原的入侵、生存、生长和转移,避免它们被免疫系统识别和攻击。因此,IDO1抑制对于免疫疗法是一个潜在的治疗目标。在该研究中,我们采用基于蛋白质结构和基于分子对接的虚拟筛选策略发现了DC-I028,活性测试表明其具有中等的活性(IC_(50)=21.61μM)。通过基于相似性和SMARTS搜索,我们购买了所有的DC-I028的衍生物,并测试了对Hela细胞的抑制活性以探究其构效关系。基于DC-I028的结构活性关系和预测的结合模式,我们得出DC-I028是一种新颖骨架的IDO1小分子抑制剂。
[Abstract]:Indoleamine 2n 3 dioxygenase 1(Indolemine 2n 3 dioxygenase IDO1) is an intracellular monomeric enzyme containing hemin, which is located in two domain domains, responsible for the initial and rate limiting steps of catalyzing the degradation of L-tryptophan through canine uric acid pathway.This reaction occurs through the oxidation of the tryptophan indole ring, which is catalyzed by IDO _ 1, IDO _ 2 and TDO, respectively, in mammals.The catalytic reaction resulted in a series of metabolites of bioactive substances, including neurotransmitter 5-hydroxytryptamine, quinolinic acid, melatonin N-methyl-Daspartic acid receptor antagonist,The end product of canine uric acid and nicotinamide adenine dinucleotide. T cells are sensitive to tryptophan degradation and tryptophan metabolite accumulation. IDO1 can inhibit the proliferation and differentiation of T cells by catabolizing tryptophan.In fact, it has been found that IDO1 is overexpressed in many human cancer cells, such as breast cancer, prostate cancer, lung cancer and rectal cancer.In addition, it was found that IDO1 was expressed in antigen-presenting cells and played a role in enhancing peripheral tolerance of tumor-associated antigens in tumor draining lymph nodes.Through these mechanisms, IDO1 promotes the invasion, survival, growth and metastasis of malignant tumor cells expressing tumor-associated antigens to prevent them from being recognized and attacked by the immune system.Therefore, IDO 1 inhibition is a potential therapeutic target for immunotherapy.In this study, a virtual screening strategy based on protein structure and molecular docking was used to find DC-I028. The activity test showed that DC-I028 was of moderate activity.Based on similarity and SMARTS search, we purchased all derivatives of DC-I028 and tested their inhibitory activity on Hela cells to explore their structure-activity relationship.Based on the structure-activity relationship of DC-I028 and the predicted binding mode, we conclude that DC-I028 is a novel skeleton IDO1 small molecule inhibitor.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91

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