鱼腥草中抗血栓活性生物碱成分的虚拟筛选
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摘要
抗血栓是预防和治疗心血管疾病的有效方法之一。基于传统中医理论、作者前期研究和相关文献,发现鱼腥草中生物碱类成分具有潜在的抗血栓活性,但是其药效物质基础和作用机制尚未明确。该研究采用分子对接技术虚拟筛选鱼腥草生物碱抗血栓的药效物质,搜集现已经从鱼腥草中报道的70个生物碱类化合物组成配体化合物库,选择P2Y1,P2Y12,凝血因子FⅪa,凝血因子FⅩa,PAR1,凝血酶等10个与血栓形成密切相关且具有已知晶体结构的靶蛋白作为受体数据库,以Drug Bank中对各靶蛋白有抑制作用并已上市或者即将上市的小分子药物为阳性对照化合物,设定各靶蛋白对应的已上市小分子药物最低打分(S)为阈值,应用Molecular Operating Environment软件(MOE,version 2016)的Dock功能进行分子对接,虚拟筛选出对接评分(S)低于阈值的化合物。对比分析了原配体、已上市药物和鱼腥草生物碱作用于各靶蛋白的主要活性位点,初步揭示了鱼腥草抗血栓活性的作用机制,为抗血栓类药物的研发提供了一定的参考。
Antithrombus is one of the effective methods to prevent and treat cardiovascular diseases. Based on the theory of traditional Chinese medicine,the author's previous research and relevant literature,it was found that the alkaloids in Houttuynia cordata has potential antithrombotic effect. However,the pharmacological substance basis and antithrombotic mechanism of H. cordata have not been clarified. In this study,molecular docking was used for virtual screening of antithrombotic alkaloids from H. cordata. Seventy alkaloids selected from H. cordata were screened in the docking ligand data-base with teen thrombosis targets with known crystal structures as the receptors. In addition,the small-molecule approved or to be approved drugs of targets from Drug Bank database were set as a positive reference with minimum score(S value) of each target's approved or to be approved drugs as threshold. The Dock module in Molecular Operating Environment(Version 2016) software was applied to screen the potential active compounds which their scores(S value) were lower than the minimum score of reference. At last the mechanism of antithrombotic effect was preliminarily revealed by compared the main active sites of the test alkaloids with original ligands and references. This study provided some useful information to development of antithrombus drugs.
Antithrombus is one of the effective methods to prevent and treat cardiovascular diseases. Based on the theory of traditional Chinese medicine,the author's previous research and relevant literature,it was found that the alkaloids in Houttuynia cordata has potential antithrombotic effect. However,the pharmacological substance basis and antithrombotic mechanism of H. cordata have not been clarified. In this study,molecular docking was used for virtual screening of antithrombotic alkaloids from H. cordata. Seventy alkaloids selected from H. cordata were screened in the docking ligand data-base with teen thrombosis targets with known crystal structures as the receptors. In addition,the small-molecule approved or to be approved drugs of targets from Drug Bank database were set as a positive reference with minimum score(S value) of each target's approved or to be approved drugs as threshold. The Dock module in Molecular Operating Environment(Version 2016) software was applied to screen the potential active compounds which their scores(S value) were lower than the minimum score of reference. At last the mechanism of antithrombotic effect was preliminarily revealed by compared the main active sites of the test alkaloids with original ligands and references. This study provided some useful information to development of antithrombus drugs.
引文
[1] World Health Statistics 2018:monitoring health for the SDGs[EB/OL].[2018-06-06]. https://www. who. int/gho/publications/world_health_statistics/2018/en/.
[2]陈可冀,李连达,翁维良,等.血瘀证与活血化瘀研究[J].中西医结合心脑血管病杂志,2005,3(1):1.
[3]舒宇,刘同华.抗凝血药物在脑卒中防治中的研究进展[J].中国药房杂志,2013,24(20):1917.
[4]唐利,向毅,杜潇,等.抗血栓药物临床应用研究进展[J].心血管病进展,2016,37(6):672.
[5]石雕,彭延古.抗血栓中药的研究现状[J].湖南中医药大学学报,2011,31(9):75.
[6]中国药典.一部[S].2015:224.
[7]江苏新医学院.中药大辞典[M].上海:上海科技出版社,1986:1439.
[8]贾梅,郑传柱,张丽,等.四物汤对急性血瘀模型大鼠活血祛瘀有效部位筛选[J].中国实验方剂学杂志,2015,21(16):119.
[9]李静,陈长勋,高阳,等.鱼腥草素抗炎与抗动脉硬化作用的探索[J].中成药,2010,32(1):26.
[10]刘敏,蒋跃平,刘韶.鱼腥草中生物碱化学成分及其生物活性研究进展[J].天然产物研究与开发,2018,30:141.
[11] Jong J,Jean M. Alkaloids from Houttuyniae Cordata[J]. J Chin Chem Soc,1993,40:301.
[12] Wei Q,Wu F,Li J,et al. Alkaloids from Houttuynia cordata and their antiplatelet aggregation activities[J]. Chin J Nat Med,2011,9:425.
[13] Kim S,Ryu S,No J,et al. Cytotoxic alkaloids from Houttuynia cordata[J]. Arch Pharm Res,2001,24:518.
[14] Chou S,Su C,Ku Y,et al. The constituents and their bioactivities of Houttuynia cordata[J]. Chem Pharm Bull,2009,57:1227.
[15] Jiang Y,Lu Y,Zhang Y,et al. Anti-complementary constituents of Houttuynia cordata and their targets in complement activation cascade[J]. Nat Prod Res,2014,28:407.
[16] Proebstle A,Bauer R. Aristolactams and a 4,5-dioxoaporphine derivative from Houttuynia cordata[J]. Planta Med,1992,58(6):568.
[17] Meng J,Yin K,Dong X,et al. Simultaneous quantification of eight bioactive components of Houttuynia cordata and related Saururaceae medicinal plants by on-line high performance liquid chromatography-diode array detector-electrospray mass spectrometry[J]. Fitoterapia,2009,80(8):468.
[18]陈少丹,高昊,卢传坚,等.鱼腥草中生物碱和酰胺类成分的研究[J].沈阳药科大学学报,2013,30(11):846.
[19] Ahn J,Chae H,Chin Y,et al. Alkaloids from aerial parts of Houttuynia cordata and their anti-inflammatory activity[J].Bioorg Med Chem Lett,2017,27:2807.
[20] Ma Q,Wei R,Wang Z,et al,Bioactive alkaloids from the aerial parts of Houttuynia cordata[J]. J Ethnopharmol, 2017,195:166.
[21] Bauer R,Probstle A,Lotter H,et al. Cyclooxygenase inhibitory constituents from Houttuynia cordata[J]. Phytomedicine,1996,2:305.
[22] NishiyaH,Ishiwata K,Komatsu K,et al. Platelet aggregation inhibitors from Jyuyaku(Houttuyniae Herb)[J]. Chem Pharm Bull,1988,36(5):1902.
[23] Qu W,Liang J,Li M. Chemical constituents from Houttuynia cordata[J]. Chin J Nat Med,2009,7:425.
[24]王利勤,赵友兴,周露,等.鱼腥草的化学成分研究[J].中草药,2007,38(12):1788.
[25] Prostle A,Neszmelyi A,Jerkovich G,et al. Novel pyridine and1,4-dihydropyridine alkaloids from Houttuynia cordata[J]. Nat Prod Lett,1994,4:235.
[26]赵琦.基于分子对接技术的小分子-蛋白质相互作用研究[D].无锡:江南大学,2009.
[27] Gohlke H,Hendlich M,Klebe G. Knowledge-based scoring function to predict protein-ligand interactions[J]. J Mol Biol,2000,295(2):337.
[28] Sagi K,Fujita K,Sugiki M,et al. Optimization of a coagulation factor VⅡa inhibitor found in factorⅩa inhibitor library[J].Bioorg Med Chem,2005,13:1487.
[29] Vijaykumar D,Sprengeler A,Shaghafi M,et al. Discovery of novel hydroxy pyrazole based factor IXa inhibitor[J]. Bioorg Med Chem Lett,2006,16(10):2796.
[30] Donald J,Pinto P,Michael J,et al. Discovery of a parenteral small molecule coagulation factor XIa inhibitor clinical candidate(BMS-962212)[J]. J Med Chem,2017,60(23):9703.
[31] Baurand A,Gachet C. The P2Y(1)receptor as a target for new antithrombotic drugs:a review of the P2Y(1)antagonist MRS-2179[J]. Cardiovasc Drug Rev,2003,21(1):67.
[2]陈可冀,李连达,翁维良,等.血瘀证与活血化瘀研究[J].中西医结合心脑血管病杂志,2005,3(1):1.
[3]舒宇,刘同华.抗凝血药物在脑卒中防治中的研究进展[J].中国药房杂志,2013,24(20):1917.
[4]唐利,向毅,杜潇,等.抗血栓药物临床应用研究进展[J].心血管病进展,2016,37(6):672.
[5]石雕,彭延古.抗血栓中药的研究现状[J].湖南中医药大学学报,2011,31(9):75.
[6]中国药典.一部[S].2015:224.
[7]江苏新医学院.中药大辞典[M].上海:上海科技出版社,1986:1439.
[8]贾梅,郑传柱,张丽,等.四物汤对急性血瘀模型大鼠活血祛瘀有效部位筛选[J].中国实验方剂学杂志,2015,21(16):119.
[9]李静,陈长勋,高阳,等.鱼腥草素抗炎与抗动脉硬化作用的探索[J].中成药,2010,32(1):26.
[10]刘敏,蒋跃平,刘韶.鱼腥草中生物碱化学成分及其生物活性研究进展[J].天然产物研究与开发,2018,30:141.
[11] Jong J,Jean M. Alkaloids from Houttuyniae Cordata[J]. J Chin Chem Soc,1993,40:301.
[12] Wei Q,Wu F,Li J,et al. Alkaloids from Houttuynia cordata and their antiplatelet aggregation activities[J]. Chin J Nat Med,2011,9:425.
[13] Kim S,Ryu S,No J,et al. Cytotoxic alkaloids from Houttuynia cordata[J]. Arch Pharm Res,2001,24:518.
[14] Chou S,Su C,Ku Y,et al. The constituents and their bioactivities of Houttuynia cordata[J]. Chem Pharm Bull,2009,57:1227.
[15] Jiang Y,Lu Y,Zhang Y,et al. Anti-complementary constituents of Houttuynia cordata and their targets in complement activation cascade[J]. Nat Prod Res,2014,28:407.
[16] Proebstle A,Bauer R. Aristolactams and a 4,5-dioxoaporphine derivative from Houttuynia cordata[J]. Planta Med,1992,58(6):568.
[17] Meng J,Yin K,Dong X,et al. Simultaneous quantification of eight bioactive components of Houttuynia cordata and related Saururaceae medicinal plants by on-line high performance liquid chromatography-diode array detector-electrospray mass spectrometry[J]. Fitoterapia,2009,80(8):468.
[18]陈少丹,高昊,卢传坚,等.鱼腥草中生物碱和酰胺类成分的研究[J].沈阳药科大学学报,2013,30(11):846.
[19] Ahn J,Chae H,Chin Y,et al. Alkaloids from aerial parts of Houttuynia cordata and their anti-inflammatory activity[J].Bioorg Med Chem Lett,2017,27:2807.
[20] Ma Q,Wei R,Wang Z,et al,Bioactive alkaloids from the aerial parts of Houttuynia cordata[J]. J Ethnopharmol, 2017,195:166.
[21] Bauer R,Probstle A,Lotter H,et al. Cyclooxygenase inhibitory constituents from Houttuynia cordata[J]. Phytomedicine,1996,2:305.
[22] NishiyaH,Ishiwata K,Komatsu K,et al. Platelet aggregation inhibitors from Jyuyaku(Houttuyniae Herb)[J]. Chem Pharm Bull,1988,36(5):1902.
[23] Qu W,Liang J,Li M. Chemical constituents from Houttuynia cordata[J]. Chin J Nat Med,2009,7:425.
[24]王利勤,赵友兴,周露,等.鱼腥草的化学成分研究[J].中草药,2007,38(12):1788.
[25] Prostle A,Neszmelyi A,Jerkovich G,et al. Novel pyridine and1,4-dihydropyridine alkaloids from Houttuynia cordata[J]. Nat Prod Lett,1994,4:235.
[26]赵琦.基于分子对接技术的小分子-蛋白质相互作用研究[D].无锡:江南大学,2009.
[27] Gohlke H,Hendlich M,Klebe G. Knowledge-based scoring function to predict protein-ligand interactions[J]. J Mol Biol,2000,295(2):337.
[28] Sagi K,Fujita K,Sugiki M,et al. Optimization of a coagulation factor VⅡa inhibitor found in factorⅩa inhibitor library[J].Bioorg Med Chem,2005,13:1487.
[29] Vijaykumar D,Sprengeler A,Shaghafi M,et al. Discovery of novel hydroxy pyrazole based factor IXa inhibitor[J]. Bioorg Med Chem Lett,2006,16(10):2796.
[30] Donald J,Pinto P,Michael J,et al. Discovery of a parenteral small molecule coagulation factor XIa inhibitor clinical candidate(BMS-962212)[J]. J Med Chem,2017,60(23):9703.
[31] Baurand A,Gachet C. The P2Y(1)receptor as a target for new antithrombotic drugs:a review of the P2Y(1)antagonist MRS-2179[J]. Cardiovasc Drug Rev,2003,21(1):67.