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新型氟代PTP1B抑制剂的设计、合成及活性研究
王保程
Subtype硕士
Thesis Advisor史大永
2016-05-24
Degree Grantor中国科学院大学
Place of Conferral北京
Degree Discipline生物工程
Keyword糖尿病 氟代化合物 Ptp1b抑制剂 计算机辅助药物设计 分子对接
Other Abstract        糖尿病患者血糖长期过高,会导致机体不同器官及组织受损或功能失调。2型糖尿病是我国成年群体,特别是中老年人群体中常见的慢性病。蛋白酪氨酸磷酸酶1B(PTP1B)作为胰岛素信号通路的负调控因子,是2型糖尿病的重要靶点。研究安全、高效的靶向PTP1B的新药成为2型糖尿病治疗的新途径。
氟原子拥有的极强的电负性,将其引入到前体药物分子中,可以改善药代动力学性质,提高生物利用度。针对靶点蛋白进行含氟化合物的分子设计,成为药物开发及结构改造优化的重要研究方向之一。
        1)本文以海洋天然产物BPN为基本骨架,以开发具有更好PTP1B抑制效果的含氟抑制剂为目标,通过计算机辅助分子设计结合理性设计,对65个含氟化合物进行筛选。化合物结构经过ChemBioDraw 和Chemdraw 3D软件处理,在PyMOL和MGL Tool中对化合物和受体蛋白进行编辑,运行AutoGrid和AutoDock进行受体蛋白和配体分子之间的对接区域的确定和分子对接。根据分子对接结果,我们根据模拟所得半抑制浓度,结合能大小,结合位点及是否存在氢键筛选了五个化合物:b18, b19, b59, b33b65
         2)我们对筛选出的五个化合物进行合成路线的设计,探索了化合物合成条件,进行了合成方法的优化。经过溴代、氧化还原、傅克烷基化等反应,完成了目标化合物(3-溴-2-(2, 3-二溴-4, 5-二甲氧基苄基)-4, 5-二甲氧基苄基)苯甲醇,1, 2, 4-三溴-3-(2-溴-3-氟-6-甲苯)-5, 6-二甲氧基苯,4-(4-溴-2, 3-二甲氧基-6-甲基苯)-2-氟苯酚,2-(4-溴-2, 3-二甲基-6-甲苯)-6-氟苯酚,2-溴-3-(3, 4-二氟苯)-1-氟-4-甲苯,2-(3, 5-二(三氟甲基)苯甲基)-3-溴-4-氟-1-甲基苯的合成。通过1H NMR和13C NMR确定了化合物的结构。
        3)对所合成化合物进行了体外PTP1B抑制活性的测定和构效关系分析。发现化合物活性与氟原子个数及取代位点有关。在一定范围内,氟原子个数的增加引起化合物活性的增加。间位以及间位和对位被氟或三氟甲基取代的化合物表现出更好的抑制活性。该测试结果与之前的分子对接结果有高度一致性。化合物b33抑制效果最好。
        本文通过计算机辅助药物分子设计和理性设计(Rational Design)相结合的方法,进行化合物抑制活性的模拟筛选,选择了五个化合物。对化合物进行了化学合成,并进行了体外活性测试和构效关系研究。期望本论文的工作能够为含氟PTP1B抑制剂的研究提供相关经验和方法参考。;          Diabetes is one of common metabolic diseases. As the main feature, blood glucose of patients is always beyond the normal range. Long-term high blood sugar would cause damage to the body's organs and tissues, such as the eyes, kidneys, blood vessels, nervous system damage or function of the heart and chronic disorders. At present, some insulin sensitizers appear to promote the development of clinical research in the treatment of type 2 diabetes. Protein tyrosine phosphatase 1B is an emerging therapeutic target for diabetes protein. Introduction of fluorine (or fluorine-containing groups, such as trifluoromethyl) is a new approach for fast-tracking drug development and optimization of structural transformation
          With the goal of higher activity fluorinated protein tyrosine phosphatase 1 B inhibitors, we designed and synthesized compounds by molecular docking instruction, and tested the in vitro activity of PTP1B.
          Firstly, we designed a series of compounds based on the basic skeleton of marine natural product BPN. We performed Computer Aided Drug Design molecular docking for the screening of better structure. We use ChemBioDraw and Chemdraw 3D software to fit compound structures as molecular docking requirements. With  PyMOL and MGL Tool, we prepared *.pdbqt file as AutoGrid required. Run AutoGrid determined docking area of ​​the receptor protein and ligand molecules. Run AutoDock to perform molecular docking. According to the results of molecular docking we selected five compounds.
          We designed the synthesis route for the selected compounds by the result of computer simulation screening. After bromination, oxidation-reduction, Friedel-Crafts alkylation reaction to complete the target compound (3-bromo-2-(2, 3-dibromo-4, 5-dimethoxybenzyl)-4, 5-dimethoxyphenyl)methanol, 1, 2, 4-tribromo-3-(2-bromo-3-fluoro-6-methylbenzyl)-5, 6-dimethoxybenzene, 4-(4-bromo-2, 3-dimethoxy-6-methylbenzyl)-2-fluorophenol, 2-(4-bromo-2, 3-dimethyl-6-toluene)-6-fluoro-phenol, 2-bromo-3-(3, 4-difluorobenzyl)-1-fluoro-4-methylbenzene, 2-(3, 5-bis(trifluoromethyl)benzyl)-3-bromo-4-fluoro-1-methyl-benzene.
           Then we performed in vitro PTP1B inhibitory activity of these compounds. The meta-fluorinated and para-fluorinated compounds showed better inhibitory activity.
           Through computer-aided drug design of molecular docking methods performed screening compounds to inhibit the activity of the PTP1B. Computer-aided drug design greatly accelerated the process of drug design and development. Provides experience and research methods for further study on the fluorinated PTP1B inhibitor.
Subject Area药学
Language中文
Document Type学位论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/112550
Collection实验海洋生物学重点实验室
Affiliation中国科学院海洋研究所
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
王保程. 新型氟代PTP1B抑制剂的设计、合成及活性研究[D]. 北京. 中国科学院大学,2016.
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