基于新型细胞因子CKLF1-CCR4小分子抑制剂的设计、合成与筛选
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摘要
北京大学人类疾病基因研究中心利用减数抑制杂交技术以PHA刺激U937细胞,首次在国际上成功克隆出一个新的具有趋化活性的细胞因子,即趋化素样因子1(chemokine-like factor 1,CKLF1)。CKLF1属于人类趋化素样因子超家族(chemokine-likefactor super family,CKLFSF)成员,CKLF1引起的炎性反应尤其和哮喘发病某病程的病理改变相似。而CKLF1末端多肽与CKLF1具有相同的受体,表现出CKLF1的拮抗作用。对CKLF1结构与功能进行深入研究,具有重要的理论研究意义和潜在的应用价值。
本论文根据上述结果,采用计算机辅助药物设计手段进行了基于结构的药物设计研究:采用同源模建方法基于氨基酸一级序列构建受体CCR4的三维结构,以氨基酸残基保守性来保证序列比对的可靠性,以疏水性标度和同源蛋白密度图方法修正了模建结构;采用了折叠识别和从头预测两种方法基于CKLF1-C19的一级氨基酸序列模建了CKLF1-C19在近天然环境中可能的三维结构;对受体采用相关突变分析的方法预测了其可能的结合位点,对配体则进行了二级结构稳定性的预测和溶剂可及化表面分析,发现二者有着相匹配的电性表面区域。采用分子对接方法研究受体配体相互作用,以电性互补特征结构约束对接结果,大概率对接事件推测出配体对于与受体结合而言可能的关键氨基酸残基——一个三肽片段。以此三肽片段作为小分子化合物的设计先导,模拟该小肽分子的空间和电性分布设计了两种结构类型的化合物——硫脲类和2-氨基噻唑类。
共合成68个新结构类型的目标化合物。硫脲类目标物由异硫氰酸酯片段和由盖布瑞尔法制得的伯胺加成获得,2-氨基噻唑类目标物以1,3-二氯丙酮和硫脲环合的产物4-氯甲基-2-氨基噻唑偶联酰氯和仲胺得到。它们的结构均经MS、~1H-NMR波谱确证。同时对目标化合物的合成工艺进行了研究和优化。
采用Boyden小室法和毛细管电泳法分别在细胞和分子水平对化合物进行了生物活性评价。研究结果表明:所合成化合物对CCR4天然配体-CCR4的相互作用有不同程度的影响,其中9、12、23、27、38#等5个化合物对CCR4三种天然配体的趋化作用均有抑制作用。
根据生物活性评价结果,进行了初步的构效关系分析。其中硫脲类结构的趋化抑制活性较优;多杂原子中心和碱性N原子之间的链接臂空间上以3个碳原子链长的趋化抑制活性为最佳;芳基侧链部分以取代有极性基团的芳杂环基趋化抑制活性为优。这些信息,这对进一步开发CCR4广谱抑制剂具有一定的指导意义。
总体来说,通过本课题的研究,表明计算机辅助药物设计手段为从蛋白到小分子药物的获得提供了一个便捷可信的途径,使得药物研究更加理性化,这可在一定程度上减少药物研究的盲目性。
PKU human disease genomics center has identified a novel cytokine CKFL1 by SSH technology in PHA-stimulated U937 cell.It is a member of chemokine-like factor super family.This genefamily is a new human gene discovered firstly by our nation internatio -nally.CKLF1 could introduce phathology change such as the situation during the last period of asthma.The C-terminal of CKLF1 could interact with the same receptor as CKLF1,and shows antagonist activity.It would be of theoretical significance and potential value that research on structure and function of CKLF1.
This thesis,in which computer aided drug design method was used,is based on those pharmacological results.3D structure of CCR4 was obtained by homology modeling; conservative residues were used to make sure the multiple sequence alignment accuracy; density map and hydrophobicity plot were used to adjust the orientations of transmembrane regions.3D structures in nature condition of C 19 were got by folding recognition and ab initio prediction.After that,the active sites of CCR4 were predicted by correlation muta -tion analysis.The solvent assess surface of C19 had been analyzed;and the secondary structure stabilization had been studied,which were both used to give the clue of C 19 key residues.Restricted by the electric surface complementary,C19 was docked to CCR4.Key residues of C19,which were frequently combined to CCR4,were found.Those residues constituted a triple peptide.In order to mimic this triple peptide,thiourea and 2-aminothi -zole cores were designed.
68 new compounds have been synthesized,all of which were confirmed by MS and ~1H-NMR.Thiourea derivatives were gained through the addition of isothiocyanate and primary amino.2-aminothizole derivatives were prepared by combinating secondary aminos and carbonyl chlorides to 2-amino-4-Chloromethyl-thizole.The routes for prepar -ing those target molecules were optimized at the mean time.
Their bioactivities were screened by both of boyden small cell method and capillary electrophoresis method.They showed different potential activity against CCR4.Especially Compound 9,12,23,27 and 38# can interrupt the interaction of all three nature ligands to CCR4.
Quantity and structure relationships were analyzed.It is showed that the thiourea structure molecules are better;the best linker length is 3-carbon length;heteroarmatic part is better than aromatic attachment as a side chain.All of these messages could be guidance for further research of CCR4 antagonists.
Above all,CADD technology supplies us convinent and reliable strategies from protein sequence to target molecules,and they could make drug research reasonable in dark.
本论文根据上述结果,采用计算机辅助药物设计手段进行了基于结构的药物设计研究:采用同源模建方法基于氨基酸一级序列构建受体CCR4的三维结构,以氨基酸残基保守性来保证序列比对的可靠性,以疏水性标度和同源蛋白密度图方法修正了模建结构;采用了折叠识别和从头预测两种方法基于CKLF1-C19的一级氨基酸序列模建了CKLF1-C19在近天然环境中可能的三维结构;对受体采用相关突变分析的方法预测了其可能的结合位点,对配体则进行了二级结构稳定性的预测和溶剂可及化表面分析,发现二者有着相匹配的电性表面区域。采用分子对接方法研究受体配体相互作用,以电性互补特征结构约束对接结果,大概率对接事件推测出配体对于与受体结合而言可能的关键氨基酸残基——一个三肽片段。以此三肽片段作为小分子化合物的设计先导,模拟该小肽分子的空间和电性分布设计了两种结构类型的化合物——硫脲类和2-氨基噻唑类。
共合成68个新结构类型的目标化合物。硫脲类目标物由异硫氰酸酯片段和由盖布瑞尔法制得的伯胺加成获得,2-氨基噻唑类目标物以1,3-二氯丙酮和硫脲环合的产物4-氯甲基-2-氨基噻唑偶联酰氯和仲胺得到。它们的结构均经MS、~1H-NMR波谱确证。同时对目标化合物的合成工艺进行了研究和优化。
采用Boyden小室法和毛细管电泳法分别在细胞和分子水平对化合物进行了生物活性评价。研究结果表明:所合成化合物对CCR4天然配体-CCR4的相互作用有不同程度的影响,其中9、12、23、27、38#等5个化合物对CCR4三种天然配体的趋化作用均有抑制作用。
根据生物活性评价结果,进行了初步的构效关系分析。其中硫脲类结构的趋化抑制活性较优;多杂原子中心和碱性N原子之间的链接臂空间上以3个碳原子链长的趋化抑制活性为最佳;芳基侧链部分以取代有极性基团的芳杂环基趋化抑制活性为优。这些信息,这对进一步开发CCR4广谱抑制剂具有一定的指导意义。
总体来说,通过本课题的研究,表明计算机辅助药物设计手段为从蛋白到小分子药物的获得提供了一个便捷可信的途径,使得药物研究更加理性化,这可在一定程度上减少药物研究的盲目性。
PKU human disease genomics center has identified a novel cytokine CKFL1 by SSH technology in PHA-stimulated U937 cell.It is a member of chemokine-like factor super family.This genefamily is a new human gene discovered firstly by our nation internatio -nally.CKLF1 could introduce phathology change such as the situation during the last period of asthma.The C-terminal of CKLF1 could interact with the same receptor as CKLF1,and shows antagonist activity.It would be of theoretical significance and potential value that research on structure and function of CKLF1.
This thesis,in which computer aided drug design method was used,is based on those pharmacological results.3D structure of CCR4 was obtained by homology modeling; conservative residues were used to make sure the multiple sequence alignment accuracy; density map and hydrophobicity plot were used to adjust the orientations of transmembrane regions.3D structures in nature condition of C 19 were got by folding recognition and ab initio prediction.After that,the active sites of CCR4 were predicted by correlation muta -tion analysis.The solvent assess surface of C19 had been analyzed;and the secondary structure stabilization had been studied,which were both used to give the clue of C 19 key residues.Restricted by the electric surface complementary,C19 was docked to CCR4.Key residues of C19,which were frequently combined to CCR4,were found.Those residues constituted a triple peptide.In order to mimic this triple peptide,thiourea and 2-aminothi -zole cores were designed.
68 new compounds have been synthesized,all of which were confirmed by MS and ~1H-NMR.Thiourea derivatives were gained through the addition of isothiocyanate and primary amino.2-aminothizole derivatives were prepared by combinating secondary aminos and carbonyl chlorides to 2-amino-4-Chloromethyl-thizole.The routes for prepar -ing those target molecules were optimized at the mean time.
Their bioactivities were screened by both of boyden small cell method and capillary electrophoresis method.They showed different potential activity against CCR4.Especially Compound 9,12,23,27 and 38# can interrupt the interaction of all three nature ligands to CCR4.
Quantity and structure relationships were analyzed.It is showed that the thiourea structure molecules are better;the best linker length is 3-carbon length;heteroarmatic part is better than aromatic attachment as a side chain.All of these messages could be guidance for further research of CCR4 antagonists.
Above all,CADD technology supplies us convinent and reliable strategies from protein sequence to target molecules,and they could make drug research reasonable in dark.
引文
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