棓单宁类化合物抗单纯疱疹病毒1型的作用及其构效关系研究
|
摘要
目的：
本研究主要研究南药的系列提取物抗单纯疱疹病毒(Herpes Simplex Virus,HSV)1型的药效学活性,并且利用计算机辅助药物设计的方法,探讨桔单宁类化合物抗HSV-1的定量构效关系,为开发新型的抗单纯疱疹病毒药物提供理论依据。
方法：
1.利用MTT(四甲基偶氮唑蓝)法检测南药提取物对Vero细胞的毒性作用；利用细胞病变效应(Cytopathic Effect, CPE)法与空斑减数法(Plaque Re-duction Assay, PRA)检测南药提取物抗HSV-1的活性。
2.在本课题组的前期工作基础上,结合文献提供的桔单宁类化合物抑制HSV-1的活性数据信息,建立桔单宁类化合物抗HSV-1的结构-活性数据库。
3.利用2D-QSAR研究方法,探讨化合物中与生物活性密切相关的原子连接片段；
4.利用3D-QSAR研究方法(包括CoMFA以及CoMSIA),建立定量构效关系模型,探讨化合物的不同力场对其活性的影响。
结果：
1.南药提取物中有部分样品显示出了较好的抗HSV-1的活性,其中余甘子果实提取物(SML-P14-E1)、直杆桉果实提取物(SML-P18-E2,SML-P18-E3)和番石榴叶子提取物(SML-P44)四个样品的治疗指数(TI值)均大于15。
2.构建了桔单宁类化合物对HSV-1抑制作用的2D-QSAR模型(其交叉验证系数q2为0.808,相关系数R2为0.900,标准偏差为0.146,最佳组分数为3,分子全息长度为151),证明该2D-QSAR模型能够很好地描述化合物中与生物活性密切相关的原子片段与活性之间的关系。
3.利用CoMFA方法来建立桔单宁类化合物抗HSV-1病毒活性的3D-QSAR模型,该模型交叉验证系数q2=0.370,相关系数R2=0.951,标准偏差为0.102,最佳组分数为3。由于该模型交叉验证系数q2=0.370<0.4,故该模型的预测能力较差,不予采用。
4.使用CoMSIA方法证实桔单宁类化合物的疏水场、静电场和氢键受体场与其对HSV-1的抑制活性存在明显的相关性。该模型的交叉验证系数q2=0.660(>0.6,表明该模型预测能力较好),相关系数R2=0.943,标准偏差为0.116,最佳组分数为4。
结论：
1.南药提取物中存在一些有潜力的活性成分,如余甘子、直杆桉、番石榴等植物来源的提取物,可供进一步的研究。
2.在桔单宁类化合物对HSV-1的抑制活性的构效关系研究中,2D-QSAR模型能够利用桔单宁类化合物分子中原子的连接方式来描述其抑制HSV-1的构效关系；同时,3D-QSAR模型能够通过桔单宁类化合物分子周围不同的力场来描述其构效关系。
3.从所构建的2D及3D-QSAR模型,结果表明,桔单宁类化合物中没食子酰基与化合物抗HSV-1病毒的活性密切相关,该类化合物的疏水场对于其抗病毒活性非常重要,疏水基团的引入有利于该类化合物对HSV-1病毒的抑制活性。
Objective:
To evaluate anti-HSV-1 activities of a series of extracts from nanyao, and use of computer-aided drug design approach to study the quantitative structure-activity relationship of the gallic tannins as HSV-1 inhibitors, to provide theoretical basis for the development of novel antiviral drugs.
Methods:
1) Cytotoxic effects of the extracts from nanyao on Vero cells were determined by MTT (3-{4,5-dimethylthiazol-2-y}-2-5-diphenytetrazolium bromide) method. Anti-viral activities of the extracts were examined by cytopathic effect (CPE) observation and plaque reduction assay (PRA).
2) Based on the previous work of our team, combined with the literatures which reported anti-HSV-1 activities of gallic tannins, the structure-activity database of gallic tannins was established.
3) 2D-QSAR model was established by using HQSAR method, to explore the molecular fragments which were closely related to the bio-activity of the compounds.
4) 3D-QSAR model was established by using CoMFA and CoMSIA methods, to investigate the relationship between different force fields of the compounds and its bio-activities.
Results:
1) Some of the extracts from nanyao have showed anti-HSV-1 activity, especially extracts from the fruits of Phyllanthus emblica (SML-P14-E1), fruits of Eucalyptus maideni (SML-P18-E2, SML-P18-E3) and leaves of Psidium guajava L. (SML-P44). All of these samples'TI values are higher than 15.
2) The 2D-QSAR model showed that the cross-validated coefficient q2 was 0.808, the non cross-validation R2 was 0.900, the standard deviation SE was 0.146, component was 3, best length was 151, which means the 2D-QSAR model have good predictive ability.
3) 3D-QSAR model, which was established by CoMFA method, showed that the cross-validated coefficient q2 was 0.370, the non cross-validation R2 was 0.951, the standard deviation SE was 0.102, and component was 3. In this model, the q2 was smaller than 0.4, which indicated the predictive ability of this model is not good enough. Accordingly, the CoMFA model was rejected.
4) 3D-QSAR model which was build using CoMSIA method showed that the cross-validated coefficient q2 was 0.660, the non cross-validation R2 was 0.943, the standard deviation SE was 0.116, and component was 4. In this model, the q2 was higher than 0.6, demonstrated this model have good predictive ability. In this CoMSIA model, evidence showed the hydrophobic field, hydrogen acceptor and electrostatic field of gallic tannins have great relevant with the anti-HSV-1 activities.
Conclusion:
1) There are some active constituents among the extracts for further research, such as Phyllanthus emblica (SML-P14-E1), Eucalyptus maideni (SML-P18-E2, SML-P18-E3) and Psidium guajava L. (SML-P44).
2) Evaluation of the gallic tannins as HSV-1 inhibitor structure-activity relationship revealed the 2D and 3D-QSAR models can be used in this research.
3) According to the models, galloyl played an important role on antiviral activity. Meanwhile, hydrophobic field was very essential. Hydrophobic groups can be helpful to increase the anti-HSV-1 activity of gallic tannins.
本研究主要研究南药的系列提取物抗单纯疱疹病毒(Herpes Simplex Virus,HSV)1型的药效学活性,并且利用计算机辅助药物设计的方法,探讨桔单宁类化合物抗HSV-1的定量构效关系,为开发新型的抗单纯疱疹病毒药物提供理论依据。
方法：
1.利用MTT(四甲基偶氮唑蓝)法检测南药提取物对Vero细胞的毒性作用；利用细胞病变效应(Cytopathic Effect, CPE)法与空斑减数法(Plaque Re-duction Assay, PRA)检测南药提取物抗HSV-1的活性。
2.在本课题组的前期工作基础上,结合文献提供的桔单宁类化合物抑制HSV-1的活性数据信息,建立桔单宁类化合物抗HSV-1的结构-活性数据库。
3.利用2D-QSAR研究方法,探讨化合物中与生物活性密切相关的原子连接片段；
4.利用3D-QSAR研究方法(包括CoMFA以及CoMSIA),建立定量构效关系模型,探讨化合物的不同力场对其活性的影响。
结果：
1.南药提取物中有部分样品显示出了较好的抗HSV-1的活性,其中余甘子果实提取物(SML-P14-E1)、直杆桉果实提取物(SML-P18-E2,SML-P18-E3)和番石榴叶子提取物(SML-P44)四个样品的治疗指数(TI值)均大于15。
2.构建了桔单宁类化合物对HSV-1抑制作用的2D-QSAR模型(其交叉验证系数q2为0.808,相关系数R2为0.900,标准偏差为0.146,最佳组分数为3,分子全息长度为151),证明该2D-QSAR模型能够很好地描述化合物中与生物活性密切相关的原子片段与活性之间的关系。
3.利用CoMFA方法来建立桔单宁类化合物抗HSV-1病毒活性的3D-QSAR模型,该模型交叉验证系数q2=0.370,相关系数R2=0.951,标准偏差为0.102,最佳组分数为3。由于该模型交叉验证系数q2=0.370<0.4,故该模型的预测能力较差,不予采用。
4.使用CoMSIA方法证实桔单宁类化合物的疏水场、静电场和氢键受体场与其对HSV-1的抑制活性存在明显的相关性。该模型的交叉验证系数q2=0.660(>0.6,表明该模型预测能力较好),相关系数R2=0.943,标准偏差为0.116,最佳组分数为4。
结论：
1.南药提取物中存在一些有潜力的活性成分,如余甘子、直杆桉、番石榴等植物来源的提取物,可供进一步的研究。
2.在桔单宁类化合物对HSV-1的抑制活性的构效关系研究中,2D-QSAR模型能够利用桔单宁类化合物分子中原子的连接方式来描述其抑制HSV-1的构效关系；同时,3D-QSAR模型能够通过桔单宁类化合物分子周围不同的力场来描述其构效关系。
3.从所构建的2D及3D-QSAR模型,结果表明,桔单宁类化合物中没食子酰基与化合物抗HSV-1病毒的活性密切相关,该类化合物的疏水场对于其抗病毒活性非常重要,疏水基团的引入有利于该类化合物对HSV-1病毒的抑制活性。
Objective:
To evaluate anti-HSV-1 activities of a series of extracts from nanyao, and use of computer-aided drug design approach to study the quantitative structure-activity relationship of the gallic tannins as HSV-1 inhibitors, to provide theoretical basis for the development of novel antiviral drugs.
Methods:
1) Cytotoxic effects of the extracts from nanyao on Vero cells were determined by MTT (3-{4,5-dimethylthiazol-2-y}-2-5-diphenytetrazolium bromide) method. Anti-viral activities of the extracts were examined by cytopathic effect (CPE) observation and plaque reduction assay (PRA).
2) Based on the previous work of our team, combined with the literatures which reported anti-HSV-1 activities of gallic tannins, the structure-activity database of gallic tannins was established.
3) 2D-QSAR model was established by using HQSAR method, to explore the molecular fragments which were closely related to the bio-activity of the compounds.
4) 3D-QSAR model was established by using CoMFA and CoMSIA methods, to investigate the relationship between different force fields of the compounds and its bio-activities.
Results:
1) Some of the extracts from nanyao have showed anti-HSV-1 activity, especially extracts from the fruits of Phyllanthus emblica (SML-P14-E1), fruits of Eucalyptus maideni (SML-P18-E2, SML-P18-E3) and leaves of Psidium guajava L. (SML-P44). All of these samples'TI values are higher than 15.
2) The 2D-QSAR model showed that the cross-validated coefficient q2 was 0.808, the non cross-validation R2 was 0.900, the standard deviation SE was 0.146, component was 3, best length was 151, which means the 2D-QSAR model have good predictive ability.
3) 3D-QSAR model, which was established by CoMFA method, showed that the cross-validated coefficient q2 was 0.370, the non cross-validation R2 was 0.951, the standard deviation SE was 0.102, and component was 3. In this model, the q2 was smaller than 0.4, which indicated the predictive ability of this model is not good enough. Accordingly, the CoMFA model was rejected.
4) 3D-QSAR model which was build using CoMSIA method showed that the cross-validated coefficient q2 was 0.660, the non cross-validation R2 was 0.943, the standard deviation SE was 0.116, and component was 4. In this model, the q2 was higher than 0.6, demonstrated this model have good predictive ability. In this CoMSIA model, evidence showed the hydrophobic field, hydrogen acceptor and electrostatic field of gallic tannins have great relevant with the anti-HSV-1 activities.
Conclusion:
1) There are some active constituents among the extracts for further research, such as Phyllanthus emblica (SML-P14-E1), Eucalyptus maideni (SML-P18-E2, SML-P18-E3) and Psidium guajava L. (SML-P44).
2) Evaluation of the gallic tannins as HSV-1 inhibitor structure-activity relationship revealed the 2D and 3D-QSAR models can be used in this research.
3) According to the models, galloyl played an important role on antiviral activity. Meanwhile, hydrophobic field was very essential. Hydrophobic groups can be helpful to increase the anti-HSV-1 activity of gallic tannins.
引文
[1]http://jpkc.hrbmu.edu.cn/weisw/index_Textbook_33_Pathogenic Viruses 08.html
[2]http://www.bbioo.com/Photo/2005/138.htm
[3]Guy H, Sabine Hr, Helga R. Antivirals against DNA viruses (hepatitis B and the herpes viruses) [J]. Current Opinion in Pharmacology 2004,4:453-464.
[4]石碧,狄莹.植物多酚[M].科学出版社,2000,1
[5]孙达旺.植物单宁化学[M]. 中国林业出版社,1992,3
[6]E.Haslam. Plant polyphenols-vegetable tannins revisted [J]. Cambridge Uni Press, 1989:10.
[7]Huh JE, Lee EO, Kim MS, et al. Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis:roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways [J]. Carcinogenesis,2005:26(8):1436-1445.
[8]Hu H, Lee HJ, Jiang C, et al. Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo[J]. Mol Cancer Ther,2008,7(9):2681-2691.
[9]Kuo PT, Lin TP, Liu LC, et al. Penta-O-galloyl-beta-D-glucose suppresses prostate cancer bone metastasis by transcriptionally repressing EGF-induced MMP-9 expression[J]. JAgric Food Chem,2009,57(8):3331-3339.
[10]Miyamoto K, Kishi N, Koshiura R, et al. Relationship between the structures and the antitumor activities of tannins[J]. Chem Pharm Bull,1987,35(2):814-822.
[11]Mukhtar H, Ahmad N. Tea polyphenols:prevention of cancer and optimizing health [J]. Am J Clin Nutr,2000,71(6):1698.
[12]Yang CS, Chung JY, Yang Q et al. Tea and tea polyphenols in cancer prevention [J]. J Nutr,2000,130(2):472S.
[13]Yoshida T, Chou T, Matsuda M, et al. Woodfordin D and oenothein A trimeric hydrolyzable tannins of macro ring structure with antitumor activity[J]. Chem
Pharm Bull,1991,39(5):1157-1162.
[14]Chen WJ, Chang CY, Lin JK. Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip) [J]. Biochem Pharmacol.2003,65(11):1777-1785.
[15]Hua KT, Way TD, Lin JK. Pentagalloylglucose inhibits estrogen receptor alpha by lysosome-dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF-7 cells [J]. Mol Carcinog.2006,45(8):551-560.
[16]PanMH, Lin JH, Lin-Shiau SY, Lin JK. Induction of apoptosis by penta-O-galloyl-beta-D-glucose through activation of caspase-3 in human leukemia HL-60 cells [J]. Eur J Pharmacol.1999,381(2-3):171-183.
[17]Chen WJ, Lin JK. Induction of Gl arrest and apoptosis in human jurkat T cells by pentagalloylglucose through inhibiting proteasome activity and elevating p27Kipl, p21Cip1/WAF1, and Bax proteins[J]. J Biol Chem.2004,279(14): 13496-13505.
[18]Kitagawa S, Nabekura T, Nakamura Y, et al. Inhibition of P-glycoprotein function by tannic acid and pentagalloylglucose [J]. J Pharm Pharmacol.2007,59(7): 965-969.
[19]Oh GS, Pae HO, Choi BM, et al..Penta-O-galloyl-beta-D-glucose inhibits phorbol myristate acetate-induced interleukin-8[correction of intereukin-8] gene expression in human monocytic U937 cells through its inactivation of nuclear factor-kappaB [J]. Int Immuno-pharmacol.2004,4(3):377-386.
[20]Kang DG, Moon MK, Choi DH, et al. Vasodilatory and anti-inflammatory effects of the 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) via a nitric oxide-cGMP pathway [J]. Eur J Pharmacol,2005,524(1-3):111-119.
[21]Pan MH, Lin-Shiau SY, Ho CT, Lin JH, Lin JK. Suppression of lipopoly-saccharide-induced nuclear factor-kappaB activity by theaflavin-3,3'-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages[J]. Bio-chem Pharmacol,2000,59(4):357-367.
[22]Koichi Ono, Tetsuya Sawada, Yoshikuni Murata, et al. Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits gastric H+, K+-ATPase[J]. Clinica Chimica Acta,2000,290:159-167.
[23]Zhang F, Luo SY, Ye YB, et al. The antibacterial efficacy of an aceraceous plant [Shantung maple (Acer truncatum Bunge)] may be related to inhibition of bacterial beta-oxoacyl-acyl carrier protein reductase (FabG) [J]. Biotechnol Appl Biochem,2008,51(Pt 2):73-78.
[24]Thabet Yangui, Ali Rhouma, Mohamed Ali Triki,et al. Control of damping-off caused by Rhizoctonia solani and Fusarium solani using olive mill waste water and some of its indigenous bacterial strains[J]. Crop Protection,2008,27(2): 189-197
[25]Tsutomu Hatano, Miwako Kusuda, Kazutoshi Inada, et al. Effects of tannins and related polyphenols on methicillin-resistant Staphylococcus aureus[J]. Phyto-chemistry,2008,66(17):2047-2055
[26]Tsutomu Hatano, Mayumi Tsugawa, Miwako Kusuda, et al. Enhancement of antibacterial effects of epigallocatechin gallate, using ascorbic acid[J]. Phyto-chemistry,2008,69(18):3111-3116
[27]Mahboba B. Naili, Rabia O. Alghazeer, Nabil A. Saleh, et al. Evaluation of antibacterial and antioxidant activities of Artemisia campestris (Astraceae) and Ziziphus lotus (Rhamnacea)[J].Arabian Journal of Chemistry,2010,3(2):79-84
[28]Xudong Li, Wei Zhang, Xuebin Qiao, et al. Prediction of binding for a kind of non-peptic HCV NS3 serine protease inhibitors from plants by molecular docking and MM-PBSA method[J]. Bioorganic & Medicinal Chemistry,2007,15(1): 220-226
[29]Deliang Duan, Zhengquan Li, Hongpeng Luo, et al. Antiviral compounds from traditional Chinese medicines Galla Chinese as inhibitors of HCV NS3 protease[J]. Bioorg. Med. Chem. Lett,2004,14:6041-604.
[30]Lee SJ, Lee HK, Jung MK, Mar W. In vitro antiviral activity of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose against hepatitis B virus [J]. Biol Pharm Bull. 2006,29(10):2131-2134.
[31]Gui-Feng Wang, Li-Ping Shi, Yu-Dan Ren, et al. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro[J]. Antiviral Research,2009,83(2):186-190
[32]Ahn MJ, Kim CY, Lee JS, et al. Inhibition of HIV-1 integrase by galloyl glucoses from Terminalia chebula and flavonol glycoside gallates from Euphorbia pekinensis [J]. PlantaMed.2002,68(5):457-459.
[33]Nakashima H, Ichiyama K, Hirayama F, et al. Sulfated pentagalloyl glucose (Y-ART-3) inhibits HIV replication and cytopathic effects in vitro, and reduces HIV infection in hu-PBL-SCID mice[J]. Antivir Res,1996,30(2-3):95-108.
[34]Chien-Min Yang, Hua-Yew Cheng, Ta-Chen Lin, et al. The in vitro activity of geraniin and 1,3,4,6-tetra-O-galloyl-β-D-glucoseisolated from Phyllanthus urinaria against herpes simplex virus type 1 and type 2 infection [J]. Journal of Ethnopharmacology,2007,110:555-558.
[35]Young Bae Ryu, Jang Hoon Kim, Su-Jin Park, et al. Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis [J]. Bioorganic & Medicinal Chemistry Letters,2010,20(3):971-974.
[36]Hiroshi Fukuhara, Yuzuri Tsurumaki, Yasushi Ino, et al. Enhanced efficacy of oncolytic herpes simplex virus(HSV-1) armed with IL-12 renal cell carcinoma models [J]. The Journal of Urology,2009,181(4):153.
[37]Debprasad Chattopadhyay, Mahmud Tareq Hassan Khan. Ethnomedicines and ethnomedicinal phytophores against herpesviruses [J]. Biotechnology Annual Review,2008,14:297-348.
[38]Hansch C, Muir RM, Fujlta T, et al. The correlation of biological activity of Plant growth regulation and chloromycetin derivatives with hammet constants and partition coeffieients [J]. J. Anl. Chem. Soc.,1963,85(18):2817-2824.
[39]Hansch C, Fujita T. F-s-P analysis. A method for the correlation of biological activity and chemical structure [J]. J Am. Chem, Soe.,1964,86(8):1616-1626.
[40]Hanseh C. A quantitative approach to biochemical structure-activity relationships [J]. Acct Chem Res.,1969,2(8):232-239.
[41]Free S.H., Wilson J.W. A mathematical contribution to structure-activity studies [J]. J Med Chem,1964,7(4):395-399.
[42]Crippen GM. Distance geometry approach to rationalizing binding data[J]. J.Med. Chem,1979,22(8):988-997.
[43]HoPfillger A.J. A QSAR investigation of dihydrofolate reduetase inbition by Baker triazines based upon molecular analysis [J]. J Am Chem Soe,1980, 102(24):7196-7206.
[44]Cramer R D, Paterson D E, Bunee J D. Comparative molecular field analysis (COMFA).1.Effect of shape on binding of steroids to carrier proteins [J]. J Am Chem Soe,1988,110(18):5959-5967.
[45]Klebe G, Abraham U, Mietzner T. Molecular similarity Indices in a comparative analysis (CoMSIA) of drug Molecules to correlate and Predict their biological activity [J]. J Med Chem,1994,37(24):4130-4146.
[46]Andrew G. Mercader, Alicia B. Pomilio. QSAR study of flavonoids and biflavo-noids as influenza H1N1 virus neuraminidase inhibitors [J]. European Journal of Medicinal Chemistry,2010,45:1724-1730.
[47]Vidya Pawar, Deepak Lokwani, Shashikant Bhandari, et al. Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies[J]. Bioorganic & Medicinal Chemistry, Available online 23 March 2010.
[48]傅继华.病毒学实用实验技术[M]. 山东科学技术出版社,2001.
[49]Nitta K,Shiota H,Nito T,Mimura Y. Sensitivities of other antiviral drugs and thymidine kinase activity of aciclovir-resistant herpes simplex virus typel[J]. Jpn Ophthalmol Soc,1994,98(6):513-519.
[50]刘晓丽,赵谋明.余甘子果汁活性成分与抗氧化活性研究[J].食品与发酵工
业,2006,32(5)：151-154
[51]邓才彬,谢庆娟,曲中堂.余甘子化学成分研究[J].中国药房,2009,20(27)：2120-2121
[52]梁清蓉.番石榴叶中酚类物质的研究[D].江南大学硕士论文,2005.
[53]彭珊珊,龙洁梅,苏丽莹.番石榴叶、番薯叶中多糖的提取与测定[J].食品科技,2006,9：106-108
[54]付辉政,罗永明,张东明.番石榴叶化学成分研究[J].中国中药杂志,2009,34(5)：577-579
[55]Hou A J, Liu Y Z, Yang H, et al. Hydrolyzable tannins and related polyohenols from Eucalyptus globulus [J]. Journal of Asian Natural Product research,2000,2 (3):205-212.
[56]谈满良,周立刚,汪冶,等.桃金娘科植物抗菌成分的研究进展[J].西北农林科技大学学报(自然科学版),2005,33(增)：225-229.
[57]陈斌,朱梅,邢旺兴,等.蓝桉果实化学成分的研究[J].中国中药杂志,2002,27(8)：496-500.
[58]向阳飞.酰基化葡萄糖HSV活性及其作用机制初步研究[D].广州：暨南大学,2009.
[59]Chien-Min Yang, Hua-Yew Cheng, Ta-Chen Lin, et al. The in vitro activity of geraniin and 1,3,4,6-tetra-O-galloyl-β-D-glucose isolated from Phyllanthus urinaria against herpes simplex virus type 1 and type 2 infection [J]. Journal of Ethnopharmacology,2007,110:555-558.
[60]Kunihiko Fukuchi, Hiroshi Sakagemi, Takuo Okuda, et al. Inhibition of herpes simplex virus infection by tannins and related compounds [J]. Ativiral Research, 1989,11:285-298.
[61]C.Hansch, A. R. Steward, S. M. Anderson, etc. The Structure-Activity Relation-ship in Barbiturates and Its Similarity to That in Other Narcotics [J]. Journal of medicinal chemistry,1967,10(5):745-753.
[62]Winker, D, Burden F. Quantitative Structre-Activity Relationships [M].1998,7: 224-31.
[63]Shridhar S. Kulkarni, Maulik R. Patel, Tanaji T. Talele. CoMFA and HQSAR studies on 6,7-dimethoxy-4-pyrrolidylquinazoline derivatives as phosphor-diesterase 10A inhibitors [J]. Bioorganic & Medicinal Chemistry,2008,16(7): 3675-3686.
[64]Weiliang Zhu, Gang Chen, Lihong Hu. QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR [J]. Bioorganic & Medicinal Chemistry,2005,13(2):313-322.
[65]Anna A. Frid, Edwin J. Matthews. Prediction of drug-related cardiac adverse effects in humans-B:Use of QSAR programs for early detection of drug-induced cardiac toxicities [J]. Regulatory Toxicology and Pharmacology,2010,56(3): 276-289.
[66]Mohammad Hossein Keshavarz. Novel method for predicting densities of polynitro arene and polynitro heteroarene explosives in order to evaluate their detonation performance [J]. Journal of Hazardous Materials,2009,165,(1-3): 579-588
[67]Cramer RD 3rd, Patterson DE, Bunce JD. Recent advances in comparative molecular field analysis (CoMFA) [J]. Prog Clin Res,1989,291:161-165.
[68]Doddareddy MR, Cho YS, Koh HY, et al. CoMFA and CoMSIA 3D QSAR analysis on N1-arysulfonylindole compounds as 5-HT6 antagonista. Bioorg Med Chem.2004,12(15):3977-3985.
[69]李仁利.药物构效关系[M].中国医药科技出版社,2004,1.
[70]Klebe G, Abraham U. Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries [J]. J Comput Aided Mol Des,1999,13(1):1-10.
[71]Dotchinova IA, Flower DR. Toward the quantitative prediction of T-cell epitopes: CoMFA and CoMSIA study of petides with affinity for the class Ⅰ MHC molecule HLA-A*0201[J]. J Med Chem,2001,44(22):3572-3581.
[72]Klebe G, Bonora GM, Toniolo C, et al. Molecular similarity indices in a comparatitive analysis (CoMSIA) of drug molecules to correlate and predict their biological activity[J]. J Med Chem,1994,37(24):4130-4146.
[73]Bismara C, Bonora GM, Toniolo C, et al. Synthetic homo-oligomethionine chemoattractants [J]. Int J Pept Protein Res,1985,26(5):482-492.
[74]Martin J, Andrews P. Comformation-activity relationships of opiate analgesics. J Comput Aided Mol Des,1987,1(1):53-72.
[75]Raghavan K, Buolamwini JK, Fesen MR, et al. Three-dimensional quantitative structure-activity relationship (QSAR) of HIV integrase inhibitors:a comparative molecular field analysis (CoMFA) study. J Med Chem,1995,38(6):890-897.
[76]Kim KH, Greco G, Novellino E, et al. Use of the hydrogen bond potential func-tion in a comparative molecular field analysis (CoMFA) on a set of benzodiaze-pines [J]. J Comput Aided Mol Des,1993,7(3):263-280.
[77]Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays [J]. Immunol Methods,1983, 65 (1):55-63.
[2]http://www.bbioo.com/Photo/2005/138.htm
[3]Guy H, Sabine Hr, Helga R. Antivirals against DNA viruses (hepatitis B and the herpes viruses) [J]. Current Opinion in Pharmacology 2004,4:453-464.
[4]石碧,狄莹.植物多酚[M].科学出版社,2000,1
[5]孙达旺.植物单宁化学[M]. 中国林业出版社,1992,3
[6]E.Haslam. Plant polyphenols-vegetable tannins revisted [J]. Cambridge Uni Press, 1989:10.
[7]Huh JE, Lee EO, Kim MS, et al. Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis:roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways [J]. Carcinogenesis,2005:26(8):1436-1445.
[8]Hu H, Lee HJ, Jiang C, et al. Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo[J]. Mol Cancer Ther,2008,7(9):2681-2691.
[9]Kuo PT, Lin TP, Liu LC, et al. Penta-O-galloyl-beta-D-glucose suppresses prostate cancer bone metastasis by transcriptionally repressing EGF-induced MMP-9 expression[J]. JAgric Food Chem,2009,57(8):3331-3339.
[10]Miyamoto K, Kishi N, Koshiura R, et al. Relationship between the structures and the antitumor activities of tannins[J]. Chem Pharm Bull,1987,35(2):814-822.
[11]Mukhtar H, Ahmad N. Tea polyphenols:prevention of cancer and optimizing health [J]. Am J Clin Nutr,2000,71(6):1698.
[12]Yang CS, Chung JY, Yang Q et al. Tea and tea polyphenols in cancer prevention [J]. J Nutr,2000,130(2):472S.
[13]Yoshida T, Chou T, Matsuda M, et al. Woodfordin D and oenothein A trimeric hydrolyzable tannins of macro ring structure with antitumor activity[J]. Chem
Pharm Bull,1991,39(5):1157-1162.
[14]Chen WJ, Chang CY, Lin JK. Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip) [J]. Biochem Pharmacol.2003,65(11):1777-1785.
[15]Hua KT, Way TD, Lin JK. Pentagalloylglucose inhibits estrogen receptor alpha by lysosome-dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF-7 cells [J]. Mol Carcinog.2006,45(8):551-560.
[16]PanMH, Lin JH, Lin-Shiau SY, Lin JK. Induction of apoptosis by penta-O-galloyl-beta-D-glucose through activation of caspase-3 in human leukemia HL-60 cells [J]. Eur J Pharmacol.1999,381(2-3):171-183.
[17]Chen WJ, Lin JK. Induction of Gl arrest and apoptosis in human jurkat T cells by pentagalloylglucose through inhibiting proteasome activity and elevating p27Kipl, p21Cip1/WAF1, and Bax proteins[J]. J Biol Chem.2004,279(14): 13496-13505.
[18]Kitagawa S, Nabekura T, Nakamura Y, et al. Inhibition of P-glycoprotein function by tannic acid and pentagalloylglucose [J]. J Pharm Pharmacol.2007,59(7): 965-969.
[19]Oh GS, Pae HO, Choi BM, et al..Penta-O-galloyl-beta-D-glucose inhibits phorbol myristate acetate-induced interleukin-8[correction of intereukin-8] gene expression in human monocytic U937 cells through its inactivation of nuclear factor-kappaB [J]. Int Immuno-pharmacol.2004,4(3):377-386.
[20]Kang DG, Moon MK, Choi DH, et al. Vasodilatory and anti-inflammatory effects of the 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) via a nitric oxide-cGMP pathway [J]. Eur J Pharmacol,2005,524(1-3):111-119.
[21]Pan MH, Lin-Shiau SY, Ho CT, Lin JH, Lin JK. Suppression of lipopoly-saccharide-induced nuclear factor-kappaB activity by theaflavin-3,3'-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages[J]. Bio-chem Pharmacol,2000,59(4):357-367.
[22]Koichi Ono, Tetsuya Sawada, Yoshikuni Murata, et al. Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits gastric H+, K+-ATPase[J]. Clinica Chimica Acta,2000,290:159-167.
[23]Zhang F, Luo SY, Ye YB, et al. The antibacterial efficacy of an aceraceous plant [Shantung maple (Acer truncatum Bunge)] may be related to inhibition of bacterial beta-oxoacyl-acyl carrier protein reductase (FabG) [J]. Biotechnol Appl Biochem,2008,51(Pt 2):73-78.
[24]Thabet Yangui, Ali Rhouma, Mohamed Ali Triki,et al. Control of damping-off caused by Rhizoctonia solani and Fusarium solani using olive mill waste water and some of its indigenous bacterial strains[J]. Crop Protection,2008,27(2): 189-197
[25]Tsutomu Hatano, Miwako Kusuda, Kazutoshi Inada, et al. Effects of tannins and related polyphenols on methicillin-resistant Staphylococcus aureus[J]. Phyto-chemistry,2008,66(17):2047-2055
[26]Tsutomu Hatano, Mayumi Tsugawa, Miwako Kusuda, et al. Enhancement of antibacterial effects of epigallocatechin gallate, using ascorbic acid[J]. Phyto-chemistry,2008,69(18):3111-3116
[27]Mahboba B. Naili, Rabia O. Alghazeer, Nabil A. Saleh, et al. Evaluation of antibacterial and antioxidant activities of Artemisia campestris (Astraceae) and Ziziphus lotus (Rhamnacea)[J].Arabian Journal of Chemistry,2010,3(2):79-84
[28]Xudong Li, Wei Zhang, Xuebin Qiao, et al. Prediction of binding for a kind of non-peptic HCV NS3 serine protease inhibitors from plants by molecular docking and MM-PBSA method[J]. Bioorganic & Medicinal Chemistry,2007,15(1): 220-226
[29]Deliang Duan, Zhengquan Li, Hongpeng Luo, et al. Antiviral compounds from traditional Chinese medicines Galla Chinese as inhibitors of HCV NS3 protease[J]. Bioorg. Med. Chem. Lett,2004,14:6041-604.
[30]Lee SJ, Lee HK, Jung MK, Mar W. In vitro antiviral activity of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose against hepatitis B virus [J]. Biol Pharm Bull. 2006,29(10):2131-2134.
[31]Gui-Feng Wang, Li-Ping Shi, Yu-Dan Ren, et al. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro[J]. Antiviral Research,2009,83(2):186-190
[32]Ahn MJ, Kim CY, Lee JS, et al. Inhibition of HIV-1 integrase by galloyl glucoses from Terminalia chebula and flavonol glycoside gallates from Euphorbia pekinensis [J]. PlantaMed.2002,68(5):457-459.
[33]Nakashima H, Ichiyama K, Hirayama F, et al. Sulfated pentagalloyl glucose (Y-ART-3) inhibits HIV replication and cytopathic effects in vitro, and reduces HIV infection in hu-PBL-SCID mice[J]. Antivir Res,1996,30(2-3):95-108.
[34]Chien-Min Yang, Hua-Yew Cheng, Ta-Chen Lin, et al. The in vitro activity of geraniin and 1,3,4,6-tetra-O-galloyl-β-D-glucoseisolated from Phyllanthus urinaria against herpes simplex virus type 1 and type 2 infection [J]. Journal of Ethnopharmacology,2007,110:555-558.
[35]Young Bae Ryu, Jang Hoon Kim, Su-Jin Park, et al. Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis [J]. Bioorganic & Medicinal Chemistry Letters,2010,20(3):971-974.
[36]Hiroshi Fukuhara, Yuzuri Tsurumaki, Yasushi Ino, et al. Enhanced efficacy of oncolytic herpes simplex virus(HSV-1) armed with IL-12 renal cell carcinoma models [J]. The Journal of Urology,2009,181(4):153.
[37]Debprasad Chattopadhyay, Mahmud Tareq Hassan Khan. Ethnomedicines and ethnomedicinal phytophores against herpesviruses [J]. Biotechnology Annual Review,2008,14:297-348.
[38]Hansch C, Muir RM, Fujlta T, et al. The correlation of biological activity of Plant growth regulation and chloromycetin derivatives with hammet constants and partition coeffieients [J]. J. Anl. Chem. Soc.,1963,85(18):2817-2824.
[39]Hansch C, Fujita T. F-s-P analysis. A method for the correlation of biological activity and chemical structure [J]. J Am. Chem, Soe.,1964,86(8):1616-1626.
[40]Hanseh C. A quantitative approach to biochemical structure-activity relationships [J]. Acct Chem Res.,1969,2(8):232-239.
[41]Free S.H., Wilson J.W. A mathematical contribution to structure-activity studies [J]. J Med Chem,1964,7(4):395-399.
[42]Crippen GM. Distance geometry approach to rationalizing binding data[J]. J.Med. Chem,1979,22(8):988-997.
[43]HoPfillger A.J. A QSAR investigation of dihydrofolate reduetase inbition by Baker triazines based upon molecular analysis [J]. J Am Chem Soe,1980, 102(24):7196-7206.
[44]Cramer R D, Paterson D E, Bunee J D. Comparative molecular field analysis (COMFA).1.Effect of shape on binding of steroids to carrier proteins [J]. J Am Chem Soe,1988,110(18):5959-5967.
[45]Klebe G, Abraham U, Mietzner T. Molecular similarity Indices in a comparative analysis (CoMSIA) of drug Molecules to correlate and Predict their biological activity [J]. J Med Chem,1994,37(24):4130-4146.
[46]Andrew G. Mercader, Alicia B. Pomilio. QSAR study of flavonoids and biflavo-noids as influenza H1N1 virus neuraminidase inhibitors [J]. European Journal of Medicinal Chemistry,2010,45:1724-1730.
[47]Vidya Pawar, Deepak Lokwani, Shashikant Bhandari, et al. Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies[J]. Bioorganic & Medicinal Chemistry, Available online 23 March 2010.
[48]傅继华.病毒学实用实验技术[M]. 山东科学技术出版社,2001.
[49]Nitta K,Shiota H,Nito T,Mimura Y. Sensitivities of other antiviral drugs and thymidine kinase activity of aciclovir-resistant herpes simplex virus typel[J]. Jpn Ophthalmol Soc,1994,98(6):513-519.
[50]刘晓丽,赵谋明.余甘子果汁活性成分与抗氧化活性研究[J].食品与发酵工
业,2006,32(5)：151-154
[51]邓才彬,谢庆娟,曲中堂.余甘子化学成分研究[J].中国药房,2009,20(27)：2120-2121
[52]梁清蓉.番石榴叶中酚类物质的研究[D].江南大学硕士论文,2005.
[53]彭珊珊,龙洁梅,苏丽莹.番石榴叶、番薯叶中多糖的提取与测定[J].食品科技,2006,9：106-108
[54]付辉政,罗永明,张东明.番石榴叶化学成分研究[J].中国中药杂志,2009,34(5)：577-579
[55]Hou A J, Liu Y Z, Yang H, et al. Hydrolyzable tannins and related polyohenols from Eucalyptus globulus [J]. Journal of Asian Natural Product research,2000,2 (3):205-212.
[56]谈满良,周立刚,汪冶,等.桃金娘科植物抗菌成分的研究进展[J].西北农林科技大学学报(自然科学版),2005,33(增)：225-229.
[57]陈斌,朱梅,邢旺兴,等.蓝桉果实化学成分的研究[J].中国中药杂志,2002,27(8)：496-500.
[58]向阳飞.酰基化葡萄糖HSV活性及其作用机制初步研究[D].广州：暨南大学,2009.
[59]Chien-Min Yang, Hua-Yew Cheng, Ta-Chen Lin, et al. The in vitro activity of geraniin and 1,3,4,6-tetra-O-galloyl-β-D-glucose isolated from Phyllanthus urinaria against herpes simplex virus type 1 and type 2 infection [J]. Journal of Ethnopharmacology,2007,110:555-558.
[60]Kunihiko Fukuchi, Hiroshi Sakagemi, Takuo Okuda, et al. Inhibition of herpes simplex virus infection by tannins and related compounds [J]. Ativiral Research, 1989,11:285-298.
[61]C.Hansch, A. R. Steward, S. M. Anderson, etc. The Structure-Activity Relation-ship in Barbiturates and Its Similarity to That in Other Narcotics [J]. Journal of medicinal chemistry,1967,10(5):745-753.
[62]Winker, D, Burden F. Quantitative Structre-Activity Relationships [M].1998,7: 224-31.
[63]Shridhar S. Kulkarni, Maulik R. Patel, Tanaji T. Talele. CoMFA and HQSAR studies on 6,7-dimethoxy-4-pyrrolidylquinazoline derivatives as phosphor-diesterase 10A inhibitors [J]. Bioorganic & Medicinal Chemistry,2008,16(7): 3675-3686.
[64]Weiliang Zhu, Gang Chen, Lihong Hu. QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR [J]. Bioorganic & Medicinal Chemistry,2005,13(2):313-322.
[65]Anna A. Frid, Edwin J. Matthews. Prediction of drug-related cardiac adverse effects in humans-B:Use of QSAR programs for early detection of drug-induced cardiac toxicities [J]. Regulatory Toxicology and Pharmacology,2010,56(3): 276-289.
[66]Mohammad Hossein Keshavarz. Novel method for predicting densities of polynitro arene and polynitro heteroarene explosives in order to evaluate their detonation performance [J]. Journal of Hazardous Materials,2009,165,(1-3): 579-588
[67]Cramer RD 3rd, Patterson DE, Bunce JD. Recent advances in comparative molecular field analysis (CoMFA) [J]. Prog Clin Res,1989,291:161-165.
[68]Doddareddy MR, Cho YS, Koh HY, et al. CoMFA and CoMSIA 3D QSAR analysis on N1-arysulfonylindole compounds as 5-HT6 antagonista. Bioorg Med Chem.2004,12(15):3977-3985.
[69]李仁利.药物构效关系[M].中国医药科技出版社,2004,1.
[70]Klebe G, Abraham U. Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries [J]. J Comput Aided Mol Des,1999,13(1):1-10.
[71]Dotchinova IA, Flower DR. Toward the quantitative prediction of T-cell epitopes: CoMFA and CoMSIA study of petides with affinity for the class Ⅰ MHC molecule HLA-A*0201[J]. J Med Chem,2001,44(22):3572-3581.
[72]Klebe G, Bonora GM, Toniolo C, et al. Molecular similarity indices in a comparatitive analysis (CoMSIA) of drug molecules to correlate and predict their biological activity[J]. J Med Chem,1994,37(24):4130-4146.
[73]Bismara C, Bonora GM, Toniolo C, et al. Synthetic homo-oligomethionine chemoattractants [J]. Int J Pept Protein Res,1985,26(5):482-492.
[74]Martin J, Andrews P. Comformation-activity relationships of opiate analgesics. J Comput Aided Mol Des,1987,1(1):53-72.
[75]Raghavan K, Buolamwini JK, Fesen MR, et al. Three-dimensional quantitative structure-activity relationship (QSAR) of HIV integrase inhibitors:a comparative molecular field analysis (CoMFA) study. J Med Chem,1995,38(6):890-897.
[76]Kim KH, Greco G, Novellino E, et al. Use of the hydrogen bond potential func-tion in a comparative molecular field analysis (CoMFA) on a set of benzodiaze-pines [J]. J Comput Aided Mol Des,1993,7(3):263-280.
[77]Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays [J]. Immunol Methods,1983, 65 (1):55-63.