系统药理学:中医药学研究新理论和新技术
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摘要
中医药作用机制研究对发现中药治疗优势和推动现代医学的发展具有重大意义。然而,传统的基于靶点高亲和力、高选择性和强生物学效应的药物研究策略与中药和靶点的弱作用、低选择性以及中药多分子的整体性作用特点存在巨大鸿沟,难以客观揭示中药的功效基础。本文将综述系统药理学研究领域的新近研究进展,同时结合研究者的实践,重点介绍如何将系统药理学的新理论和新技术应用于中药弱结合药物的开发。通过系统分析中药"药-靶-效"的潜在规律,提出了中药"弱结合-显效"理论,建立了靶点群拓扑结构及动力学分析新方法,揭示了中药弱结合显效新模式。为从系统水平研究和分析中药的功效机制,以及新药开发,老药新用,天然产物开发利用提供了新思路。
Research on the therapeutic mechanism of Traditional Chinese Medicine(TCM) is of great significance for demonstrating the advantages of TCM and promoting the development of modern medicine. However, there is a huge gap between strategies in drug discovery based on the traditional high affinity and characteristics such as weak effects and low selectivity between Chinese materia medica and targets, multi-molecular effect of TCM, which is the difficulty to objectively reveal the efficacy mechanism of TCM. Based on new advancement of systematic pharmacology(SP) and practical researcher.s experience, this paper focused on introducing the application of new theories and new technologies of SP into the development of weak binding drugs in herbs. With the systematic analysis of the potential mechanism of the"drug-target-effect"of TCM, a new method based on network topology and dynamics analysis was established, and a novel mode of weak binding drugs in herbs was revealed, which provided new ideas for the systematic research of the efficacy mechanism of TCM, the drug discovery and drug repositioning.
Research on the therapeutic mechanism of Traditional Chinese Medicine(TCM) is of great significance for demonstrating the advantages of TCM and promoting the development of modern medicine. However, there is a huge gap between strategies in drug discovery based on the traditional high affinity and characteristics such as weak effects and low selectivity between Chinese materia medica and targets, multi-molecular effect of TCM, which is the difficulty to objectively reveal the efficacy mechanism of TCM. Based on new advancement of systematic pharmacology(SP) and practical researcher.s experience, this paper focused on introducing the application of new theories and new technologies of SP into the development of weak binding drugs in herbs. With the systematic analysis of the potential mechanism of the"drug-target-effect"of TCM, a new method based on network topology and dynamics analysis was established, and a novel mode of weak binding drugs in herbs was revealed, which provided new ideas for the systematic research of the efficacy mechanism of TCM, the drug discovery and drug repositioning.
引文
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27 Li P,Fu Y,Ru J,et al.Insights from systems pharmacology into cardiovascular drug discovery and therapy.BMC Systems Biology,2014,8(1):141.
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29 Cheng J Q,Lindsley C W,Cheng G Z,et al.The Akt/PKB pathway:molecular target for cancer drug discovery.Oncogene,2005,24(50):7482.
30 Gao Z,Hwang D,Bataille F,et al.Serine phosphorylation of insulin receptor substrate 1 by inhibitorκB kinase complex.Journal of Biological Chemistry,2002,277(50):48115-48121.
31 Nú?ez S,Venhorst J,Kruse C G,et al.Target-drug interactions:first principles and their application to drug discovery.Drug Discovery Today,2012,17(1-2):10-22.
32 Xie L,Evangelidis T,Xie L,et al.Drug discovery using chemical systems biology:weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir.PLoS Computational Biology,2011,7(4):e1002037.
33 Kitchen D B,Decornez H,Furr J R,et al.Docking and scoring in virtual screening for drug discovery:methods and applications.Nat Rev Drug Discov,2004,3(11):935-949.
34 Kollman P A,Massova I,Reyes C,et al.Calculating structures and free energies of complex molecules:combining molecular mechanics and continuum models.Acc Chem Res,2000,33(12):889-897.
35 Durrant J D,Mccammon J A.Molecular dynamics simulations and drug discovery.BMC Biol,2011,9(1):71.
36 Yu H,Chen J,Xu X,et al.A systematic prediction of multiple drug-target interactions from chemical,genomic,and pharmacological data.PLoS One,2012,7(5):e37608.
37 Zheng C,Guo Z,Huang C,et al.Large-scale Direct Targeting for Drug Repositioning and Discovery.Sci Rep,2015,5:11970.
38 Wang Y,Zheng C,Huang C,et al.Systems pharmacology dissecting holistic medicine for treatment of complex diseases:an example using cardiocerebrovascular diseases treated by TCM.Evid Based Complement Alternat Med,2015,2015(6216,supple):980190.
39 Araujo R P,Liotta L A,Petricoin E F.Proteins,drug targets and the mechanisms they control:the simple truth about complex networks.Nature Reviews Drug Discovery,2007,6(11):871-880.
40 Milo R,Shen-Orr S,Itzkovitz S,et al.Network motifs:simple building blocks of complex networks.Science,2002,298(5594):824-827.
41 Wagner A.Circuit topology and the evolution of robustness in two-gene circadian oscillators.Proc Natl Acad Sci USA,2005,102(33):11775-11780.
42 Fitzgerald J B,Schoeberl B,Nielsen U B,et al.Systems biology and combination therapy in the quest for clinical efficacy.Nat Chem Biol,2006,2(9):458-466.
43 Ma W,Trusina A,El-Samad H,et al.Defining network topologies that can achieve biochemical adaptation.Cell,2009,138(4):760-773.
44 Yin N,Ma W,Pei J,et al.Synergistic and antagonistic drug combinations depend on network topology.PLoS One,2014,9(4):e93960.
45 Wang J,Zhang C J,Chia W N,et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.Nat Commun,2015,6:10111.
46 Lawrence M C,Jivan A,Shao C,et al.The roles of MAPKs in disease.Cell Res,2008,18(4):436-442.
47 Johnson G L,Lapad A T R.Mitogen-activated protein kinase pathways mediated by ERK,JNK,and p38 protein kinases.Science,2002,298(5600):1911-1912.
48 Sabio G,Davis R J.TNF and MAP kinase signalling pathways.Semin Immunol,2014,26(3):237-245.
49 Zheng C,Wang J,Liu J,et al.System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.Mol Divers,2014,18(3):621-635.
50 Yang Y,Li Y,Wang J,et al.Systematic investigation of ginkgo biloba leaves for treating cardio-cerebrovascular diseases in an animal model.ACS Chem Biol,2017,12(5):1363-1372.
51 Li P,Chen J,Wang J,et al.Systems pharmacology strategies for drug discovery and combination with applications to cardiovascular diseases.J Ethnopharmacol,2014,151(1):93-107.
2 Medina-Franco J L,Mart Nez-Mayorga K,Giulianotti M A,et al.Visualization of the chemical space in drug discovery.Current ComputerAided Drug Design,2008,4(4):322-333.
3 Mestres J,Gregori-Puigjane E.Conciliating binding efficiency and polypharmacology.Trends Pharmacol Sci,2009,30(9):470-474.
4 Roth B L,Sheffler D J,Kroeze W K.Magic shotguns versus magic bullets:selectively non-selective drugs for mood disorders and schizophrenia.Nat Rev Drug Discov,2004,3(4):353-359.
5 Csermely P,Agoston V,Pongor S.The efficiency of multi-target drugs:the network approach might help drug design.Trends in Pharmacological Sciences,2005,26(4):178-182.
6 Liu T,Lin Y,Wen X,et al.Binding DB:a web-accessible database of experimentally determined protein-ligand binding affinities.Nucleic Acids Research,2006,35(1):198-201.
7 Ohlson S.Designing transient binding drugs:a new concept for drug discovery.Drug Discovery Today,2008,13(9-10):433-439.
8 Wang J,Zhang C-J,Chia W N,et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.Nature Communications,2015,6:10111.
9 Zhou Y,Li W,Xiao Y.Profiling of multiple targets of artemisinin activated by hemin in cancer cell proteome.ACS Chemical Biology,2016,11(4):882-888.
10 Wang J,Guo Z,Fu Y,et al.Weak-binding molecules are not drug-toward a systematic strategy for finding effective weak-binding drugs.Briefings in Bioinformatics,2017,18(2):321-332.
11 Zheng C,Wang J,Liu J,et al.System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.Molecular Diversity,2014,18(3):621-635.
12 Liu J,Sun K,Zheng C,et al.Pathway as a pharmacological target for herbal medicines:an investigation from reduning injection.PloS One,2015,10(4):e0123109.
13 Macarron R,Banks M N,Bojanic D,et al.Impact of high-throughput screening in biomedical research.Nature reviews Drug discovery,2011,10(3):188.
14 Vaynberg J,Qin J.Weak protein-protein interactions as probed by NMR spectroscopy.Trends in Biotechnology,2006,24(1):22-27.
15?zbal C C,Lamarr W A,Linton J R,et al.High throughput screening via mass spectrometry:a case study using acetylcholinesterase.Assay and Drug Development Technologies,2004,2(4):373-382.
16 Nienaber V L,Richardson P L,Klighofer V,et al.Discovering novel ligands for macromolecules using X-ray crystallographic screening.Nature Biotechnology,2000,18(10):1105.
17 Duong-Thi M-D,Meiby E,Bergstr M M,et al.Weak affinity chromatography as a new approach for fragment screening in drug discovery.Analytical Biochemistry,2011,414(1):138-146.
18 Rudnev A V,Aleksenko S S,Semenova O,et al.Determination of binding constants and stoichiometries for platinum anticancer drugs and serum transport proteins by capillary electrophoresis using the HummelDreyer method.Journal of Separation Science,2005,28(2):121-127.
19 Rich R L,Myszka D G.Higher-throughput,label-free,real-time molecular interaction analysis.Analytical Biochemistry,2007,361(1):1.
20 Xie L,Xie L,Kinnings S L,et al.Novel computational approaches to polypharmacology as a means to define responses to individual drugs.Annual review of pharmacology and toxicology,2012,52(1):361-379.
21 Barab SI A-L,Gulbahce N,Loscalzo J.Network medicine:a networkbased approach to human disease.Nature Reviews Genetics,2011,12(1):56.
22 Araujo R P,Liotta L A,Petricoin E F.Proteins,drug targets and the mechanisms they control:the simple truth about complex networks.Nature reviews Drug Discovery,2007,6(11):871.
23 Yang K,Bai H,Ouyang Q,et al.Finding multiple target optimal intervention in disease-related molecular network.Molecular Systems Biology,2008,4(1):228.
24 Fujioka A,Terai K,Itoh R E,et al.Dynamics of the Ras/ERK MAPKcascade as monitored by fluorescent probes.Journal of Biological Chemistry,2006,281(13):8917-8926.
25 Bianconi F,Baldelli E,Ludovini V,et al.Computational model of EGFRand IGF1R pathways in lung cancer:a systems biology approach for translational oncology.Biotechnology Advances,2012,30(1):142-153.
26 Hwang W C,Zhang A,Ramanathan M.Identification of information flow-modulating drug targets:a novel bridging paradigm for drug discovery.Clinical Pharmacology&Therapeutics,2008,84(5):563-572.
27 Li P,Fu Y,Ru J,et al.Insights from systems pharmacology into cardiovascular drug discovery and therapy.BMC Systems Biology,2014,8(1):141.
28 Courtney K D,Corcoran R B,Engelman J A.The PI3K pathway as drug target in human cancer.Journal of Clinical Oncology,2010,28(6):1075.
29 Cheng J Q,Lindsley C W,Cheng G Z,et al.The Akt/PKB pathway:molecular target for cancer drug discovery.Oncogene,2005,24(50):7482.
30 Gao Z,Hwang D,Bataille F,et al.Serine phosphorylation of insulin receptor substrate 1 by inhibitorκB kinase complex.Journal of Biological Chemistry,2002,277(50):48115-48121.
31 Nú?ez S,Venhorst J,Kruse C G,et al.Target-drug interactions:first principles and their application to drug discovery.Drug Discovery Today,2012,17(1-2):10-22.
32 Xie L,Evangelidis T,Xie L,et al.Drug discovery using chemical systems biology:weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir.PLoS Computational Biology,2011,7(4):e1002037.
33 Kitchen D B,Decornez H,Furr J R,et al.Docking and scoring in virtual screening for drug discovery:methods and applications.Nat Rev Drug Discov,2004,3(11):935-949.
34 Kollman P A,Massova I,Reyes C,et al.Calculating structures and free energies of complex molecules:combining molecular mechanics and continuum models.Acc Chem Res,2000,33(12):889-897.
35 Durrant J D,Mccammon J A.Molecular dynamics simulations and drug discovery.BMC Biol,2011,9(1):71.
36 Yu H,Chen J,Xu X,et al.A systematic prediction of multiple drug-target interactions from chemical,genomic,and pharmacological data.PLoS One,2012,7(5):e37608.
37 Zheng C,Guo Z,Huang C,et al.Large-scale Direct Targeting for Drug Repositioning and Discovery.Sci Rep,2015,5:11970.
38 Wang Y,Zheng C,Huang C,et al.Systems pharmacology dissecting holistic medicine for treatment of complex diseases:an example using cardiocerebrovascular diseases treated by TCM.Evid Based Complement Alternat Med,2015,2015(6216,supple):980190.
39 Araujo R P,Liotta L A,Petricoin E F.Proteins,drug targets and the mechanisms they control:the simple truth about complex networks.Nature Reviews Drug Discovery,2007,6(11):871-880.
40 Milo R,Shen-Orr S,Itzkovitz S,et al.Network motifs:simple building blocks of complex networks.Science,2002,298(5594):824-827.
41 Wagner A.Circuit topology and the evolution of robustness in two-gene circadian oscillators.Proc Natl Acad Sci USA,2005,102(33):11775-11780.
42 Fitzgerald J B,Schoeberl B,Nielsen U B,et al.Systems biology and combination therapy in the quest for clinical efficacy.Nat Chem Biol,2006,2(9):458-466.
43 Ma W,Trusina A,El-Samad H,et al.Defining network topologies that can achieve biochemical adaptation.Cell,2009,138(4):760-773.
44 Yin N,Ma W,Pei J,et al.Synergistic and antagonistic drug combinations depend on network topology.PLoS One,2014,9(4):e93960.
45 Wang J,Zhang C J,Chia W N,et al.Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.Nat Commun,2015,6:10111.
46 Lawrence M C,Jivan A,Shao C,et al.The roles of MAPKs in disease.Cell Res,2008,18(4):436-442.
47 Johnson G L,Lapad A T R.Mitogen-activated protein kinase pathways mediated by ERK,JNK,and p38 protein kinases.Science,2002,298(5600):1911-1912.
48 Sabio G,Davis R J.TNF and MAP kinase signalling pathways.Semin Immunol,2014,26(3):237-245.
49 Zheng C,Wang J,Liu J,et al.System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.Mol Divers,2014,18(3):621-635.
50 Yang Y,Li Y,Wang J,et al.Systematic investigation of ginkgo biloba leaves for treating cardio-cerebrovascular diseases in an animal model.ACS Chem Biol,2017,12(5):1363-1372.
51 Li P,Chen J,Wang J,et al.Systems pharmacology strategies for drug discovery and combination with applications to cardiovascular diseases.J Ethnopharmacol,2014,151(1):93-107.