中药中的西药成分分析及其对组合药物设计的指导意义
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摘要
考虑到世界范围内的植物分布模式极其相似以及西药中包含有大量天然药物信息的事实,我们推测尽管用于治疗同一种疾病的中药和西药的植物来源不一定相同,但是二者的活性成份在分子结构上有可能是相同或相近的。这些信息不但可以证明中药疗效是有物质基础的,更为重要的是,可以用来指导组合药物设计。
为了验证这一猜想,本论文借助化学信息学的方法、技术对中西药物化合物作了整体结构相似性比较。
通过比较中药化学(TCMD)和综合药物化学(CMC)数据库发现结构相似性大于0.85的化合物908对,其中327对是结构完全相同的;同时,比较了中药化学(TCMD)和药物开发报道数据库(MDDR)发现结构相似性大于0.85的化合物1054对,其中146对是结构完全相同的。继之对327对化合物进行活性注释,发现一些功效的记载已经有1500年的历史。
然后,我们分析了不同体系传统药物的演化历史发现。尽管东西方的医药体系相对独立发展,但在植物水平上,东西方采用同一种或同一属的某些植物药治疗相似的疾病;在分子水平上,尽管很多目前使用的分子药物不是来源于中药,但在中药植物的化学成分中发现其含有相应的活性化合物。这意味着经历了几千年演化的中、西药药学体系之间存在着趋同进化现象。
最后,通过传统中药成分、天然产物、临床药物、药物候选物的化学空间分析,我们认为寻找新化学实体将越来越困难,因此,应该转变药物研发模式,通过组合现有药物来发现新药。同时,以几个中药复方为例,探讨了中西方药物的分子水平相似性在组合药物开发中的潜在应用。
本研究不但加深了对药学体系演化规律的认识,提高中药在严格科学意义上的可信度;而且研究结果对于设计组合药物具有指导意义。
Considering the fact that the plant distribution patterns in China and other regions of the world are rather similar and Western drugs including many natural medicine information, we speculate that although Western drugs and traditional Chinese remedies origined from different herbs to treat the same conditions, but their activity components in structure is perhaps the same or similar, this information not proved traditional Chinese medicine have good effection, most importantly , it can guide the design of new combinatorial drugs.
To verify this speculation, we employed chemoinformatic methods to make a global structural comparison between～10,000 traditional Chinese medicine (TCM) components (recorded in traditional Chinese Medicine Database (TCMD)) and～8,000 modern Western drugs (recorded in Comprehensive Medicinal Chemistry (CMC) database), which revealed that 908 agent pairs are structurally similar (with similarity≥0.85). Among them, 327 agent pairs are identical in structures. Furthermore, a comparison between～10,000 TCM components and～145,000 drug candidates (recorded in MDL Drug Data Report (MDDR) database) identified 1,054 pairs of structurally similar agents (with similarity≥0.85). Among them, 146 agent pairs are identical in structures. It is interesting to note that a certain part of CMC counterparts of TCMD agents recorded in ancient Chinese medicinal book for more than 1500 years.
Secondly through comparing the herbal usage of ancient medicinal systems of different nations, we noticed that some similar herbs have been independently discovered and utilized to treat similar diseases by different cultures at herbal medicine level. At molecular level although different folks used distinct herbs to treat the same conditions, similar effective agents are responsible, at least in part, for these herbal effects. Since there was little medicinal communication between China and foreign countries 2000 years ago, we think that the existence of similar herbs and/or components in very ancient Chinese and Western medicines can be best explained as a convergent evolution in both medicinal systems.
Thirdly, we compared chemical space with the components contained in traditional medicines and natural products and taked some traditional Chinese formulae example, discussed western healers in traditional Chinese medicine of implications for finding Western drug combinations.
This research not deepen understand evolvement between two medicinal systems, improve the reliability for traditional Chinese medicine in science point of view, but the result can apply to synergistic combined drugs, and guide the discovery of new combined drugs.
为了验证这一猜想,本论文借助化学信息学的方法、技术对中西药物化合物作了整体结构相似性比较。
通过比较中药化学(TCMD)和综合药物化学(CMC)数据库发现结构相似性大于0.85的化合物908对,其中327对是结构完全相同的;同时,比较了中药化学(TCMD)和药物开发报道数据库(MDDR)发现结构相似性大于0.85的化合物1054对,其中146对是结构完全相同的。继之对327对化合物进行活性注释,发现一些功效的记载已经有1500年的历史。
然后,我们分析了不同体系传统药物的演化历史发现。尽管东西方的医药体系相对独立发展,但在植物水平上,东西方采用同一种或同一属的某些植物药治疗相似的疾病;在分子水平上,尽管很多目前使用的分子药物不是来源于中药,但在中药植物的化学成分中发现其含有相应的活性化合物。这意味着经历了几千年演化的中、西药药学体系之间存在着趋同进化现象。
最后,通过传统中药成分、天然产物、临床药物、药物候选物的化学空间分析,我们认为寻找新化学实体将越来越困难,因此,应该转变药物研发模式,通过组合现有药物来发现新药。同时,以几个中药复方为例,探讨了中西方药物的分子水平相似性在组合药物开发中的潜在应用。
本研究不但加深了对药学体系演化规律的认识,提高中药在严格科学意义上的可信度;而且研究结果对于设计组合药物具有指导意义。
Considering the fact that the plant distribution patterns in China and other regions of the world are rather similar and Western drugs including many natural medicine information, we speculate that although Western drugs and traditional Chinese remedies origined from different herbs to treat the same conditions, but their activity components in structure is perhaps the same or similar, this information not proved traditional Chinese medicine have good effection, most importantly , it can guide the design of new combinatorial drugs.
To verify this speculation, we employed chemoinformatic methods to make a global structural comparison between～10,000 traditional Chinese medicine (TCM) components (recorded in traditional Chinese Medicine Database (TCMD)) and～8,000 modern Western drugs (recorded in Comprehensive Medicinal Chemistry (CMC) database), which revealed that 908 agent pairs are structurally similar (with similarity≥0.85). Among them, 327 agent pairs are identical in structures. Furthermore, a comparison between～10,000 TCM components and～145,000 drug candidates (recorded in MDL Drug Data Report (MDDR) database) identified 1,054 pairs of structurally similar agents (with similarity≥0.85). Among them, 146 agent pairs are identical in structures. It is interesting to note that a certain part of CMC counterparts of TCMD agents recorded in ancient Chinese medicinal book for more than 1500 years.
Secondly through comparing the herbal usage of ancient medicinal systems of different nations, we noticed that some similar herbs have been independently discovered and utilized to treat similar diseases by different cultures at herbal medicine level. At molecular level although different folks used distinct herbs to treat the same conditions, similar effective agents are responsible, at least in part, for these herbal effects. Since there was little medicinal communication between China and foreign countries 2000 years ago, we think that the existence of similar herbs and/or components in very ancient Chinese and Western medicines can be best explained as a convergent evolution in both medicinal systems.
Thirdly, we compared chemical space with the components contained in traditional medicines and natural products and taked some traditional Chinese formulae example, discussed western healers in traditional Chinese medicine of implications for finding Western drug combinations.
This research not deepen understand evolvement between two medicinal systems, improve the reliability for traditional Chinese medicine in science point of view, but the result can apply to synergistic combined drugs, and guide the discovery of new combined drugs.
引文
[1]Jiang W Y.Therapeutic wisdom in traditional Chinese medicine:a perspective from modern science[J].Trends Pharmacol Sci,2005,26(11):558-563.
[2]Cheng J T.Review:drug therapy in Chinese traditional medicine[J].J Clin Pharmacol,2000,40:445-450.
[3]Botchers A T,Hackman R M,Keen C L,et al.Complementary medicine:a review of immunomodulatory effects of Chinese herbal medicines[J].Am J Clin Nutr,1997,66(6):1303-1312.
[4]Zhang H Y,Tang X C.Neuroprotective effects of huperzine A:new therapeutic targets for neurodegenerative disease[J].Trends Pharmacol Sci,2006,27(12):619-625.
[5][EB/OL].http://xys.3322.org/xys/netters/Fang-Zhouzi/bkb/zhongyi2.txt
[6]Qiu J.A culture in the balance[J].Nature,2007,448(7150):126-128.
[7]Paterson I,Anderson E A.The renaissance of natural products as drug candidates[J].Science,2005,310(5747):451-453.
[8]Newman D J,Cragg G M,Snader K M.Natural products as sources of new drugs over the period 1981-2002[J].J Nat Prod,2003,66(7):1022-1037.
[9]Butler M S.Natural products to drugs:natural product derived compounds in clinical trials[J].Nat Prod Rep,2005,22(2):162-195.
[10]陈平.中药与西药研究的相互借鉴[J].中华医学研究杂志,2004,4(8):741.
[11]张鸣皋.药学发展简史[M].北京:中国医药科技出版社,1993.
[12]万芳,钟赣生.《万物》与《五十二病方》有关药物内容的比较[J].中国医药学报,1990,5(2):55-58.
[13]朱晟,何端生.中药简史[M].桂林:广西师范大学出版社,2007.
[14]王付.《伤寒杂病论》方剂数探源[J].中医药通报,2007,6(2):26-27.
[15]李广珍,盛岱仁.中药方剂的产生与发展[J].医学纵横,1999,2:36.
[16]李广珍,盛岱仁。历代本草小考[J].医学纵横,1999,2:37.
[17]钟赣生,万芳.盖伦以前的早期药学发展概论[J].中华医史杂志,1999,29(3):178-182.
[18]卡斯蒂廖尼著,程之范主译.医学史[M].桂林:广西师范大学出版社,2003.
[19]吴立坤.近代西方药学的传入及其对中药学的影响[D]:[硕士学位论文].北京:北京中医药大学,2006.
[20]张保国,刘庆芳.中药新药研究的概况、思路及方法[J].开封医专学报,1999,18(2):48-51.
[21]郭文华,童路.试论现代植物药[J].世界科学技术-中药现代化,1999,1(3):41-43.
[22]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004年.
[23]Hughes B.2007 FDA drug approvals:a year of flux[J].Nat Rev Drug Discov,2008,7(2):107-109.
[24]Editorial.Raising the game[J].Nat Biotech,2008,26(2):137.
[25]李娜,诸黎星,邹栩.1996年～2005年全球上市新药研发趋势及分析[J].药学进展,2007,31(5):228-231.
[26]Keith C T,Bo risy A A,Stockwell B R.Multicomponent therapeutics for networked systems[J].Nat Rev Drug Discov,2005,4(1):71-78.
[27]Ideker T,Galitski T,Hood L.A new approach to decoding life:systems biology[J].Annu Rev Genomics Hum Genet,2001,2:343-372.
[28]Aebersold R,Mann M.Mass Spectrometry-based proteomics[J].Nature,2003,422(6928):198-207.
[29]Rochfort S.Metabolomics reviewed:a new "omics"platform technology for systems biology and implications for natural products research[J].J Nat Prod.2005.68(12):1813-1820.
[30]周兴旺.化学生物学新前沿——化学蛋白质组学[J].化学进展,2003,15(6):518-522.
[31]Kitano H.Computational systems biology[J].Nature,2002,420(6912):206-210.
[32]Fitzgerald J B,Schoeberl B,Nielsen U B,et al.Systems biology and combination therapy in the quest for clinical efficacy[J].Nat Chem Biol,2006,2(9):458-466.
[33]Li W F,Jiang J G,Chen J.Chinese Medicine and Its Modernization Demands[J].Arch Med Res, 2008,39(2):246-251.
[34]Wadman M.The right combination[J].Nature.2006.439(7191):390-391
[35]李彬.浅谈化学信息学[J].内蒙古石油化工,2005,1:20-21.
[36]徐筱杰.化学信息学的涵义及教育[J].大学化学,2002,17(1):38-41.
[37]宋心琦.21世纪理论化学的重要课题之我见[J].大学化学,1999,14(1):15-19.
[38]约翰·加斯泰格尔,托马斯·恩格尔著,梁逸曾等译.化学信息学教程[M],北京:化学工业出版社,2005.
[39]Sheridan R P,Kearsley S K.Why do we need so many chemical similarity search methods[J].Drug Discov Today,2002,7(17):903-911.
[40]Holliday J D,Hu C Y,Willett P.Grouping of Coefficients for the Calculation of Inter-Molecular Similarity and Dissimilarity using 2D Fragment Bit-Strings[J].Comb Chem High Throughput Screen,2002,5(2):155-166.
[41]Chen X,Brown F K.Asymmetry of Chemical Similarity[J].ChemMedChem,2007,2(2):180-182.
[42]Carbo R,Calabuig B.MOLSIMIL-88:molecular similarity calculations using a CNDO-like approximation[J].Comput Phys Commun,1989,55(1):117-126.
[43]Eckert H,Bajorath J.Molecular similarity analysis in virtual screening:foundations,limitations and novel approaches[J].Drug Discov Today,2007,12(5-6):225-233.
[44]Willett P.Similarity-based virtual screening using 2D fingerprints[J].Drug Discov Today,2006,11(23-24):1046-1053.
[45]Dean P M.Molecular similarity in drug design[M].Dordrecht:Kluwer academic pulishers,1994.London & New York:Blackie Academic & Professional,1995.
[46]Carbo-Dorca R.Molecular similarity and reactivity:from quantum chemical to phenomenological approaches understanding chemical reactivity[M].Amsterdam:Kluwer Academic Publishers,1995.
[47]Sen K.Molecular Similarity Ⅰ.Book Series Topics in Current Chemistry[M].1995.
[48]Sen K.Molecular Similarity Ⅱ.Book Series Topics in Current Chemistry[M].1995.
[49]Carbo-Dorca R,Mezey P G.Advances in Molecular Similarity[M],London:JAI Press,1996.
[50]Carbo-Dorca R,Mezey P G.Advances in Molecular Similarity[M],London:JAI Press,1998.
[51]Carbo-Dorca R,Girones X,Mezey P G.Fundamentals of Molecular Similarity[M].New York:Kluwer Academic/Plenum Publishers,2001.
[52]von Carbo-Dorca R,Robert D,Amat L,et al.Molecular Quantum Similarity in QSAR and Drug Design(Lecture Notes in Chemistry)[M].Berlin:Springer,2000.
[53]Kubinyi H,Folkers G,Martin YC.3D QSAR in Drug Design.Volume 2.Ligand-Protein Interactions and Molecular Similarity[M].Dordrecht:Kluwer Academic Publishers,1998.
[54]Gasteiger J.Handbook ofchemoinformatics[M],Weinheim:Wiley-VCH,2003.
[55]Leach A R,Gillet V J.An introduction to chemoinformatics[M],Dordrecht:Kluwer Academic Publishers,2003.
[56]Bender A,Glen R C.Molecular similarity:a key technique in molecular informatics[J].Org Biomol Chem,2004,2(22):3204-3218.
[57]Maldonado A G,Doucet J P,Petitjean M,et al.Molecular similarity and diversity in chemoinformatics:from theory to applications[J].Mol Divers,2006,10(1):39-79.
[58]Willett P,Barnard J M,Downs G M.Chemical similarity searching[J].J Chem Inf Comput Sci,1998,38(6),983-996.
[59]Walters W P,Stahl M T,Murcko M A.Virtual screening-an overview[J].Drug Discov Today,1998,3(4):160-178.
[60]Gillet V J,Wild D J,Willett P,Bradshaw J.Similarity and dissimilarity methods for processing chemical structure databases[J].The Computer Journal,1998,41(8):547-558.
[61]Dobson C M.Chemical space and biology[J].Nature,2004,432(16):824-828.
[62]黄钦,乔学斌,徐筱杰.中草药有效成分化合物的化学空间分析[J].计算机与应用化学.2007,24(1):41-44.
[63]刘树深,易忠胜.基础化学计量学[M].北京:科学出版社.1999.
[64]倪永年.化学计量学在分析化学中的应用[M].北京:科学出版社.2004.
[65]史永刚,冯新泸,李子存,化学计量学[M].北京:中国石化出版社.2003.
[66]李鸿吉.数理统计实用算法[M].北京:科学出版社.2003.
[67]SYBYL 7.0.St-louis,Missouri:Tripos Associates,Inc,2004.
[68]Accelrys Software Inc.Cerius 2.Version 4.10L,2005.
[69]Andreas Bender.Molprint 2D.2004.
[70]Andreas Bender,Hamse Y.Mussa,and Robert C.Glen.Similarity Searching of Chemical Databases Using Atom Environment Descriptors(MOLPRINT 2D):Evaluation of Performance[J].J Chem InfComput Sci,2004,44(5),1708-1718.
[71]Andreas Bender,Hamse Y,Mussa,et al.Molecular similarity searching using atom environments,information-based feature selection,and a naive bayesian classifier[J].J Chem Inf Comput Sci,2004,44(1):170-178.
[72]Molecular Networks GmbH Computerchemie.Corina.Version 3.2.
[73][EB/OL].http://www.9iv.com/down/soft/2965.html
[74]Ji Z L,Zhou H,Wang J F,et al.Traditional Chinese medicine information database[J].J Ethnopharmacol,2006,103(3):501.
[75]He M,Yan X,Zhou J,et al.Traditional Chinese medicine database and application on the Web [J].J Chem Inf Comput Sci,2001,41(2):273-277.
[76]Wang J F,Zhou H,Han L Y,et al.Traditional Chinese medicine information database[J].Clin Pharmacol Ther,2005,78(1):92-93.
[77]何敏,沈敏。中药数据库的设计与建立[J].计算机与应用化学,1999,16(5):363-364.
[78]Shen J,Xu X,Cheng F,et ai.Virtual screening on natural products for discovering active compounds and target information[J].Curr Med Chem,2003,10(21):2327-2342.
[79]Chan K.Progress in traditional Chinese medicine[J].Trends Pharmacol Sci,1995,16(6):182-187.
[80]Yuan R,Lin Y.Traditional Chinese medicine:an approach to scientific proof and clinical validation[J].Pharmacol Ther,2000,86(2):191-198.
[81]Wiseman N.Traditional Chinese medicine:a brief outline[J].J Chem Inf Comput Sci,2002,42(3):445-455.
[82]Wang M W,Hao X J,Chen K X.Biological screening of natural products and drug innovation in China[J].Phil Trans R Soc B,2007,362(1482):1093-1105.
[83]Schmidt B M,Ribnicky D M,Lipsky P E,et al.Revisiting the ancient concept of botanical therapeutics[J].Nat Chem Biol,2007,3(7):360-366.
[84]Keith C T,Borisy A A,Stockwell B R.Multicomponent therapeutics for networked systems[J].Nat Rev Drug Discov,2005,4(1):71-78.
[85]Newman D J,Cragg G M,Snader K M.The influence of natural products upon drug discovery [J].Nat Prod Rep,2000,17(3):215-234.
[86]Newman D J,Cragg G M,Snader K M.Natural product as sources of new drugs over the period 1981-2002[J].J Nat Prod,2003,66(7):1022-1037.
[87]Newman D J,Cragg G M.Natural products as sources of new drugs over the last 25 years[J].J Nat Prod,2007,70(3):461-477.
[88]Butler M S.Natural products to drugs:natural product-derived compounds in clinical trials[J].Nat Prod Rep,2005,22(2):162-195.
[89]中科院过程控制课题组.中药化学数据库[DB/OL].2005.(http://www.neotrident.com/newpage/show_paage.asp?ArticleID=973&ClassID=112&GroupID=26).
[90]Comprehensive Medicinal Chemistry(CMC),MDL Information Systems Inc.,San Leandro,CA (USA),[DB/OL].(http://www.mdl.com).2004.
[91]Molecular Drug Data Report(MDDR),MDL Information Systems Inc.,San Leandro,CA(USA),[DB/OL].(http://www.mdl.com).2004.
[92]中华本草编委会.中华本草[M].上海:上海科学技术出版社,2004.
[93]江苏新医学院.中药大辞典[M].上海:上海科学技术出版社,2005.
[94]Gainer F E,Arnett W A.Quantitative determination of acronine,an antitumor alkaloid,by gas chromatography[J].J Pharm Sci,1969,58(12):1548-1550.
[95]Dalton L K,Demerac S,Elmes B C,et al.Synthesis of the tumor-inhibitory alkaloids,ellipticine,9-methoxyellipticine,and related pyrido[4,3-b]carbazoles[J].Aust J Chem,1967,20:2715-2727.
[96]Arteaga S,Andrade-Cetto A,Cardenas R.Larrea tridentata(Creosote bush),an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid[J].J Ethnopharmacol,2005,98(3),231-239.
[97]Hartwell J L.Types of anti-cancer agents isolated from plants[J].Cancer Treat Rep,1976,60(8),1031-1067.
[98]Kavimani S,Ilango R,Madheswaran M,et al.Antitumor activity of plumbagin against Dalton's ascitic lymphoma[J].Indian J Pharm Sci,1996,58(5),194-196.
[99]Hao L H,Zhao J Y,Gao C Z,et al.The effect of β-elemene on reversal multidrug resistance and the expression of P-glycoprotein in K562/Adm[J].Acta Anat Sin,2006,37,48-51.
[100]Li D Y,Chen X Y,Liu R J.Review on constituents of traditional Chinese medicine reversing multidrug resistance in leukemia cells[J].Chin J Inform TCM,2004,11,951-954.
[101]Li J F,He T,Huang W Y,et al.Inhibitory effects of quercetin and isorhamnetin on oxidative modification of HDL induced by Cu~(2+)/Fe~(2+) in vitro[J].China Med Eng,2004 12,22-25.
[102]Avendano C,Menendez J C.Inhibitors of multidrug resistance to antitumor agents(MDR)[J].Curr Med Chem,2002,9(2):159-193.
[103]Elde N C,Long M,Turkewitz A P.A role for convergent evolution in the secretory life of cells[J].Trends Cell Biol,2007,17(4):157-164.
[104]Colosimo P F,Hosemann K E,Balabhadra S,et al.Widespread parallel evolution in sticklebacks by repeated fixation of ectodysplasin alleles[J].Science,2005,307(5717):1928-1933.
[105]Joron M,Papa R,Beltran M,et al.A conserved supergene locus controls colour pattern diversity in Heliconius butterflies[J].PLoS Biol,2006,4(10):e303.
[106]Santos J C,Coloma L A,Cannatella D C.Multiple,recurring origins of aposematism and diet specialization in poison frogs[J].Proc Natl Acad Sci USA,2003,100(22):12792-12797.
[107]袁昌齐,冯煦.欧美植物药[M].南京:东南大学出版社,2004.
[108]Chevallier A.Encyclopedia of Medicinal Plants[M],1st ed.(Translated by Liang LX,Jiang H B,Chen Y B,et al.) Guangxi Science and Technology Publishers,Nanning,China,2003.
[109]Mackowiak P A.Brief history of antipyretic therapy[J].Clin Infect Dis,2000,31(suppl 5),S154-S156.
[110]廖育群.阿育吠陀印度的传统医学[M]。沈阳:辽宁教育出版社,2002.
[111]谢志民.藜芦涌吐作用的本草考证[J].陕西中医,1991,12(4):180-181.
[112]袁昌齐,冯煦,张卫明等.非洲药用植物概述[J].中国野生植物资源,2007,26(4),23-26.
[113]Scott B R,Pathak M A,Mohn G R.Molecular and genetic basis of furocoumarin reactions[J].Mutat Res,1976,39(1):29-74.
[114]Ruffolo R R.Why has R&D productivity declined in the pharmaceutical industry[J]? Expert Opin Drug Discov,2006,1,99-102.
[115]Corson T W,Crews C M.Molecular understanding and modern application of traditional medicines:triumphs and trials[J].Cell,2007,130(5),769-774.
[116]Stermitz F R,Lorenz P,Tawara J N,et al.Synergy in a medicinal plant:antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin,a multidrug pump inhibitor[J].Proc Natl Acad Sci USA,2000,97(4):1433-1437.
[117]聂慧民.论《伤寒杂病论》的组方特色与经方创研优势[J].中医杂志,2006,47(11):806-810.
[118]Wang L,Zhou G B,Liu P,et al.Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia[J].Proc Natl Acad Sci USA,2008,105(12):4826-4831.
[119]Frantz S.The trouble with making combination drugs[J].Nat Rev Drug Discov,2006,5(11):881-882.
[120]杜冬生,杨士友.左金丸及其组分黄连和吴茱萸治疗胃肠道疾病研究进展[J].安徽医药,2007,11(8):673-675.
[121]Qiu J.Traditional medicine:A culture in the balance[J].Nature,2007,448(7150):126-128.
[122]Min Y D,Kwon H C,Yang M C,et al.Isolation of limonoids and alkaloids from Phellodendron amurense and their multidrug resistance(MDR) reversal activity[J].Arch Pharm Res,2007,30(1),58-63.
[123]Bae E A,Han M J,Kim N J,et al.Anti-Helicobacter pylori activity of herbal medicines[J].Biol Pharm Bull,1998,21(9):990-992.
[124]Shimizu N,lkehara Y,Inada KI,et al.Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian Gerbils[J].Cancer Res,2000,60(6):1512-1514.
[125]Berstein L M.Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer[J].Cancer Letters,2005,224(2):203-212.
[126]魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考[J].中华中医药杂志,2005,20(8):496.
[127]周鲁,张卫华,曾令航,等.老年性痴呆的复方用药规律研究[J].辽宁中医杂志,2005,32(3):243-244.
[128]Zhang H Y.One-compound-multiple-targets strategy to combat Alzheimer's disease[J].FEBS Lett,2005,579(24):5260-5264.
[129]Roman G C.Vascular dementia:distinguishing characteristics,treatment,and prevention[J].J Am Geriatr Soc,2003,51(5):S296-S304.
[130]Biessels G J,Deary I J,Ryan C M.Cognition and diabetes:a lifespan perspective[J].Lancet Neurol,2008,7(2):184-190.
[131]Nathan D M.Long-term complications of diabetes mellitus[J].N Engl J Med,1993,328(23):1676.
[132]林善锬.重视糖尿病肾脏病变的诊断与治疗[J].中华内分泌代谢杂志,1998,14(2):65.
[133]李以欣.成年病治疗药的开发概况(续)[J].国外医药-合成药-生化药制剂分册,1995,16(1):20.
[134]王敏.化淤降糖汤治疗糖尿病90例[J].四川中医,2005,23(9):67.
[2]Cheng J T.Review:drug therapy in Chinese traditional medicine[J].J Clin Pharmacol,2000,40:445-450.
[3]Botchers A T,Hackman R M,Keen C L,et al.Complementary medicine:a review of immunomodulatory effects of Chinese herbal medicines[J].Am J Clin Nutr,1997,66(6):1303-1312.
[4]Zhang H Y,Tang X C.Neuroprotective effects of huperzine A:new therapeutic targets for neurodegenerative disease[J].Trends Pharmacol Sci,2006,27(12):619-625.
[5][EB/OL].http://xys.3322.org/xys/netters/Fang-Zhouzi/bkb/zhongyi2.txt
[6]Qiu J.A culture in the balance[J].Nature,2007,448(7150):126-128.
[7]Paterson I,Anderson E A.The renaissance of natural products as drug candidates[J].Science,2005,310(5747):451-453.
[8]Newman D J,Cragg G M,Snader K M.Natural products as sources of new drugs over the period 1981-2002[J].J Nat Prod,2003,66(7):1022-1037.
[9]Butler M S.Natural products to drugs:natural product derived compounds in clinical trials[J].Nat Prod Rep,2005,22(2):162-195.
[10]陈平.中药与西药研究的相互借鉴[J].中华医学研究杂志,2004,4(8):741.
[11]张鸣皋.药学发展简史[M].北京:中国医药科技出版社,1993.
[12]万芳,钟赣生.《万物》与《五十二病方》有关药物内容的比较[J].中国医药学报,1990,5(2):55-58.
[13]朱晟,何端生.中药简史[M].桂林:广西师范大学出版社,2007.
[14]王付.《伤寒杂病论》方剂数探源[J].中医药通报,2007,6(2):26-27.
[15]李广珍,盛岱仁.中药方剂的产生与发展[J].医学纵横,1999,2:36.
[16]李广珍,盛岱仁。历代本草小考[J].医学纵横,1999,2:37.
[17]钟赣生,万芳.盖伦以前的早期药学发展概论[J].中华医史杂志,1999,29(3):178-182.
[18]卡斯蒂廖尼著,程之范主译.医学史[M].桂林:广西师范大学出版社,2003.
[19]吴立坤.近代西方药学的传入及其对中药学的影响[D]:[硕士学位论文].北京:北京中医药大学,2006.
[20]张保国,刘庆芳.中药新药研究的概况、思路及方法[J].开封医专学报,1999,18(2):48-51.
[21]郭文华,童路.试论现代植物药[J].世界科学技术-中药现代化,1999,1(3):41-43.
[22]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004年.
[23]Hughes B.2007 FDA drug approvals:a year of flux[J].Nat Rev Drug Discov,2008,7(2):107-109.
[24]Editorial.Raising the game[J].Nat Biotech,2008,26(2):137.
[25]李娜,诸黎星,邹栩.1996年～2005年全球上市新药研发趋势及分析[J].药学进展,2007,31(5):228-231.
[26]Keith C T,Bo risy A A,Stockwell B R.Multicomponent therapeutics for networked systems[J].Nat Rev Drug Discov,2005,4(1):71-78.
[27]Ideker T,Galitski T,Hood L.A new approach to decoding life:systems biology[J].Annu Rev Genomics Hum Genet,2001,2:343-372.
[28]Aebersold R,Mann M.Mass Spectrometry-based proteomics[J].Nature,2003,422(6928):198-207.
[29]Rochfort S.Metabolomics reviewed:a new "omics"platform technology for systems biology and implications for natural products research[J].J Nat Prod.2005.68(12):1813-1820.
[30]周兴旺.化学生物学新前沿——化学蛋白质组学[J].化学进展,2003,15(6):518-522.
[31]Kitano H.Computational systems biology[J].Nature,2002,420(6912):206-210.
[32]Fitzgerald J B,Schoeberl B,Nielsen U B,et al.Systems biology and combination therapy in the quest for clinical efficacy[J].Nat Chem Biol,2006,2(9):458-466.
[33]Li W F,Jiang J G,Chen J.Chinese Medicine and Its Modernization Demands[J].Arch Med Res, 2008,39(2):246-251.
[34]Wadman M.The right combination[J].Nature.2006.439(7191):390-391
[35]李彬.浅谈化学信息学[J].内蒙古石油化工,2005,1:20-21.
[36]徐筱杰.化学信息学的涵义及教育[J].大学化学,2002,17(1):38-41.
[37]宋心琦.21世纪理论化学的重要课题之我见[J].大学化学,1999,14(1):15-19.
[38]约翰·加斯泰格尔,托马斯·恩格尔著,梁逸曾等译.化学信息学教程[M],北京:化学工业出版社,2005.
[39]Sheridan R P,Kearsley S K.Why do we need so many chemical similarity search methods[J].Drug Discov Today,2002,7(17):903-911.
[40]Holliday J D,Hu C Y,Willett P.Grouping of Coefficients for the Calculation of Inter-Molecular Similarity and Dissimilarity using 2D Fragment Bit-Strings[J].Comb Chem High Throughput Screen,2002,5(2):155-166.
[41]Chen X,Brown F K.Asymmetry of Chemical Similarity[J].ChemMedChem,2007,2(2):180-182.
[42]Carbo R,Calabuig B.MOLSIMIL-88:molecular similarity calculations using a CNDO-like approximation[J].Comput Phys Commun,1989,55(1):117-126.
[43]Eckert H,Bajorath J.Molecular similarity analysis in virtual screening:foundations,limitations and novel approaches[J].Drug Discov Today,2007,12(5-6):225-233.
[44]Willett P.Similarity-based virtual screening using 2D fingerprints[J].Drug Discov Today,2006,11(23-24):1046-1053.
[45]Dean P M.Molecular similarity in drug design[M].Dordrecht:Kluwer academic pulishers,1994.London & New York:Blackie Academic & Professional,1995.
[46]Carbo-Dorca R.Molecular similarity and reactivity:from quantum chemical to phenomenological approaches understanding chemical reactivity[M].Amsterdam:Kluwer Academic Publishers,1995.
[47]Sen K.Molecular Similarity Ⅰ.Book Series Topics in Current Chemistry[M].1995.
[48]Sen K.Molecular Similarity Ⅱ.Book Series Topics in Current Chemistry[M].1995.
[49]Carbo-Dorca R,Mezey P G.Advances in Molecular Similarity[M],London:JAI Press,1996.
[50]Carbo-Dorca R,Mezey P G.Advances in Molecular Similarity[M],London:JAI Press,1998.
[51]Carbo-Dorca R,Girones X,Mezey P G.Fundamentals of Molecular Similarity[M].New York:Kluwer Academic/Plenum Publishers,2001.
[52]von Carbo-Dorca R,Robert D,Amat L,et al.Molecular Quantum Similarity in QSAR and Drug Design(Lecture Notes in Chemistry)[M].Berlin:Springer,2000.
[53]Kubinyi H,Folkers G,Martin YC.3D QSAR in Drug Design.Volume 2.Ligand-Protein Interactions and Molecular Similarity[M].Dordrecht:Kluwer Academic Publishers,1998.
[54]Gasteiger J.Handbook ofchemoinformatics[M],Weinheim:Wiley-VCH,2003.
[55]Leach A R,Gillet V J.An introduction to chemoinformatics[M],Dordrecht:Kluwer Academic Publishers,2003.
[56]Bender A,Glen R C.Molecular similarity:a key technique in molecular informatics[J].Org Biomol Chem,2004,2(22):3204-3218.
[57]Maldonado A G,Doucet J P,Petitjean M,et al.Molecular similarity and diversity in chemoinformatics:from theory to applications[J].Mol Divers,2006,10(1):39-79.
[58]Willett P,Barnard J M,Downs G M.Chemical similarity searching[J].J Chem Inf Comput Sci,1998,38(6),983-996.
[59]Walters W P,Stahl M T,Murcko M A.Virtual screening-an overview[J].Drug Discov Today,1998,3(4):160-178.
[60]Gillet V J,Wild D J,Willett P,Bradshaw J.Similarity and dissimilarity methods for processing chemical structure databases[J].The Computer Journal,1998,41(8):547-558.
[61]Dobson C M.Chemical space and biology[J].Nature,2004,432(16):824-828.
[62]黄钦,乔学斌,徐筱杰.中草药有效成分化合物的化学空间分析[J].计算机与应用化学.2007,24(1):41-44.
[63]刘树深,易忠胜.基础化学计量学[M].北京:科学出版社.1999.
[64]倪永年.化学计量学在分析化学中的应用[M].北京:科学出版社.2004.
[65]史永刚,冯新泸,李子存,化学计量学[M].北京:中国石化出版社.2003.
[66]李鸿吉.数理统计实用算法[M].北京:科学出版社.2003.
[67]SYBYL 7.0.St-louis,Missouri:Tripos Associates,Inc,2004.
[68]Accelrys Software Inc.Cerius 2.Version 4.10L,2005.
[69]Andreas Bender.Molprint 2D.2004.
[70]Andreas Bender,Hamse Y.Mussa,and Robert C.Glen.Similarity Searching of Chemical Databases Using Atom Environment Descriptors(MOLPRINT 2D):Evaluation of Performance[J].J Chem InfComput Sci,2004,44(5),1708-1718.
[71]Andreas Bender,Hamse Y,Mussa,et al.Molecular similarity searching using atom environments,information-based feature selection,and a naive bayesian classifier[J].J Chem Inf Comput Sci,2004,44(1):170-178.
[72]Molecular Networks GmbH Computerchemie.Corina.Version 3.2.
[73][EB/OL].http://www.9iv.com/down/soft/2965.html
[74]Ji Z L,Zhou H,Wang J F,et al.Traditional Chinese medicine information database[J].J Ethnopharmacol,2006,103(3):501.
[75]He M,Yan X,Zhou J,et al.Traditional Chinese medicine database and application on the Web [J].J Chem Inf Comput Sci,2001,41(2):273-277.
[76]Wang J F,Zhou H,Han L Y,et al.Traditional Chinese medicine information database[J].Clin Pharmacol Ther,2005,78(1):92-93.
[77]何敏,沈敏。中药数据库的设计与建立[J].计算机与应用化学,1999,16(5):363-364.
[78]Shen J,Xu X,Cheng F,et ai.Virtual screening on natural products for discovering active compounds and target information[J].Curr Med Chem,2003,10(21):2327-2342.
[79]Chan K.Progress in traditional Chinese medicine[J].Trends Pharmacol Sci,1995,16(6):182-187.
[80]Yuan R,Lin Y.Traditional Chinese medicine:an approach to scientific proof and clinical validation[J].Pharmacol Ther,2000,86(2):191-198.
[81]Wiseman N.Traditional Chinese medicine:a brief outline[J].J Chem Inf Comput Sci,2002,42(3):445-455.
[82]Wang M W,Hao X J,Chen K X.Biological screening of natural products and drug innovation in China[J].Phil Trans R Soc B,2007,362(1482):1093-1105.
[83]Schmidt B M,Ribnicky D M,Lipsky P E,et al.Revisiting the ancient concept of botanical therapeutics[J].Nat Chem Biol,2007,3(7):360-366.
[84]Keith C T,Borisy A A,Stockwell B R.Multicomponent therapeutics for networked systems[J].Nat Rev Drug Discov,2005,4(1):71-78.
[85]Newman D J,Cragg G M,Snader K M.The influence of natural products upon drug discovery [J].Nat Prod Rep,2000,17(3):215-234.
[86]Newman D J,Cragg G M,Snader K M.Natural product as sources of new drugs over the period 1981-2002[J].J Nat Prod,2003,66(7):1022-1037.
[87]Newman D J,Cragg G M.Natural products as sources of new drugs over the last 25 years[J].J Nat Prod,2007,70(3):461-477.
[88]Butler M S.Natural products to drugs:natural product-derived compounds in clinical trials[J].Nat Prod Rep,2005,22(2):162-195.
[89]中科院过程控制课题组.中药化学数据库[DB/OL].2005.(http://www.neotrident.com/newpage/show_paage.asp?ArticleID=973&ClassID=112&GroupID=26).
[90]Comprehensive Medicinal Chemistry(CMC),MDL Information Systems Inc.,San Leandro,CA (USA),[DB/OL].(http://www.mdl.com).2004.
[91]Molecular Drug Data Report(MDDR),MDL Information Systems Inc.,San Leandro,CA(USA),[DB/OL].(http://www.mdl.com).2004.
[92]中华本草编委会.中华本草[M].上海:上海科学技术出版社,2004.
[93]江苏新医学院.中药大辞典[M].上海:上海科学技术出版社,2005.
[94]Gainer F E,Arnett W A.Quantitative determination of acronine,an antitumor alkaloid,by gas chromatography[J].J Pharm Sci,1969,58(12):1548-1550.
[95]Dalton L K,Demerac S,Elmes B C,et al.Synthesis of the tumor-inhibitory alkaloids,ellipticine,9-methoxyellipticine,and related pyrido[4,3-b]carbazoles[J].Aust J Chem,1967,20:2715-2727.
[96]Arteaga S,Andrade-Cetto A,Cardenas R.Larrea tridentata(Creosote bush),an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid[J].J Ethnopharmacol,2005,98(3),231-239.
[97]Hartwell J L.Types of anti-cancer agents isolated from plants[J].Cancer Treat Rep,1976,60(8),1031-1067.
[98]Kavimani S,Ilango R,Madheswaran M,et al.Antitumor activity of plumbagin against Dalton's ascitic lymphoma[J].Indian J Pharm Sci,1996,58(5),194-196.
[99]Hao L H,Zhao J Y,Gao C Z,et al.The effect of β-elemene on reversal multidrug resistance and the expression of P-glycoprotein in K562/Adm[J].Acta Anat Sin,2006,37,48-51.
[100]Li D Y,Chen X Y,Liu R J.Review on constituents of traditional Chinese medicine reversing multidrug resistance in leukemia cells[J].Chin J Inform TCM,2004,11,951-954.
[101]Li J F,He T,Huang W Y,et al.Inhibitory effects of quercetin and isorhamnetin on oxidative modification of HDL induced by Cu~(2+)/Fe~(2+) in vitro[J].China Med Eng,2004 12,22-25.
[102]Avendano C,Menendez J C.Inhibitors of multidrug resistance to antitumor agents(MDR)[J].Curr Med Chem,2002,9(2):159-193.
[103]Elde N C,Long M,Turkewitz A P.A role for convergent evolution in the secretory life of cells[J].Trends Cell Biol,2007,17(4):157-164.
[104]Colosimo P F,Hosemann K E,Balabhadra S,et al.Widespread parallel evolution in sticklebacks by repeated fixation of ectodysplasin alleles[J].Science,2005,307(5717):1928-1933.
[105]Joron M,Papa R,Beltran M,et al.A conserved supergene locus controls colour pattern diversity in Heliconius butterflies[J].PLoS Biol,2006,4(10):e303.
[106]Santos J C,Coloma L A,Cannatella D C.Multiple,recurring origins of aposematism and diet specialization in poison frogs[J].Proc Natl Acad Sci USA,2003,100(22):12792-12797.
[107]袁昌齐,冯煦.欧美植物药[M].南京:东南大学出版社,2004.
[108]Chevallier A.Encyclopedia of Medicinal Plants[M],1st ed.(Translated by Liang LX,Jiang H B,Chen Y B,et al.) Guangxi Science and Technology Publishers,Nanning,China,2003.
[109]Mackowiak P A.Brief history of antipyretic therapy[J].Clin Infect Dis,2000,31(suppl 5),S154-S156.
[110]廖育群.阿育吠陀印度的传统医学[M]。沈阳:辽宁教育出版社,2002.
[111]谢志民.藜芦涌吐作用的本草考证[J].陕西中医,1991,12(4):180-181.
[112]袁昌齐,冯煦,张卫明等.非洲药用植物概述[J].中国野生植物资源,2007,26(4),23-26.
[113]Scott B R,Pathak M A,Mohn G R.Molecular and genetic basis of furocoumarin reactions[J].Mutat Res,1976,39(1):29-74.
[114]Ruffolo R R.Why has R&D productivity declined in the pharmaceutical industry[J]? Expert Opin Drug Discov,2006,1,99-102.
[115]Corson T W,Crews C M.Molecular understanding and modern application of traditional medicines:triumphs and trials[J].Cell,2007,130(5),769-774.
[116]Stermitz F R,Lorenz P,Tawara J N,et al.Synergy in a medicinal plant:antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin,a multidrug pump inhibitor[J].Proc Natl Acad Sci USA,2000,97(4):1433-1437.
[117]聂慧民.论《伤寒杂病论》的组方特色与经方创研优势[J].中医杂志,2006,47(11):806-810.
[118]Wang L,Zhou G B,Liu P,et al.Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia[J].Proc Natl Acad Sci USA,2008,105(12):4826-4831.
[119]Frantz S.The trouble with making combination drugs[J].Nat Rev Drug Discov,2006,5(11):881-882.
[120]杜冬生,杨士友.左金丸及其组分黄连和吴茱萸治疗胃肠道疾病研究进展[J].安徽医药,2007,11(8):673-675.
[121]Qiu J.Traditional medicine:A culture in the balance[J].Nature,2007,448(7150):126-128.
[122]Min Y D,Kwon H C,Yang M C,et al.Isolation of limonoids and alkaloids from Phellodendron amurense and their multidrug resistance(MDR) reversal activity[J].Arch Pharm Res,2007,30(1),58-63.
[123]Bae E A,Han M J,Kim N J,et al.Anti-Helicobacter pylori activity of herbal medicines[J].Biol Pharm Bull,1998,21(9):990-992.
[124]Shimizu N,lkehara Y,Inada KI,et al.Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian Gerbils[J].Cancer Res,2000,60(6):1512-1514.
[125]Berstein L M.Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer[J].Cancer Letters,2005,224(2):203-212.
[126]魏翠柏,田金洲,贾建平.老年痴呆中医病因病机理论的认识与思考[J].中华中医药杂志,2005,20(8):496.
[127]周鲁,张卫华,曾令航,等.老年性痴呆的复方用药规律研究[J].辽宁中医杂志,2005,32(3):243-244.
[128]Zhang H Y.One-compound-multiple-targets strategy to combat Alzheimer's disease[J].FEBS Lett,2005,579(24):5260-5264.
[129]Roman G C.Vascular dementia:distinguishing characteristics,treatment,and prevention[J].J Am Geriatr Soc,2003,51(5):S296-S304.
[130]Biessels G J,Deary I J,Ryan C M.Cognition and diabetes:a lifespan perspective[J].Lancet Neurol,2008,7(2):184-190.
[131]Nathan D M.Long-term complications of diabetes mellitus[J].N Engl J Med,1993,328(23):1676.
[132]林善锬.重视糖尿病肾脏病变的诊断与治疗[J].中华内分泌代谢杂志,1998,14(2):65.
[133]李以欣.成年病治疗药的开发概况(续)[J].国外医药-合成药-生化药制剂分册,1995,16(1):20.
[134]王敏.化淤降糖汤治疗糖尿病90例[J].四川中医,2005,23(9):67.