| 3,883 | 159 | 69 |
| 下载次数 | 被引频次 | 阅读次数 |
分析10年来国际上新药研发失败率达30%的原因,反思近代此类生物医药研究的哲学理念与研究模式,介绍国际上向现代生物医药研究模式转化的新趋势,即侧重综合,从功能基因组学、蛋白组学、系统生物学、网络药理学等多维视角来研究复杂疾病的病理网络,提出新药研发的策略应针对这种病理网络的多种(而非个别)相关基因及其调节蛋白进行干预才能有效影响疾病。另外,介绍国际上在"疾病-基因-靶点-药物"网络研究上的概况和基于网络药理学的药物研发新模式,包括网络药理学的分析方法和多向药理学设计策略,并对这类研究中存在的问题和挑战作了分析。
Abstract：The reasons for 30% of failures in new drug candidates being translated into effective therapies in the decade world widely were analyzed in this article. The fundamental problem might not be technological,or scientific but philosophical for the rational drug design and the research paradigm. There was a trend for integration of poly-angles,i.e. genomics,proteomics,system biology and network pharmacology in drug research and development,due to the fact that the complex disease could not be prevented by affecting a single target. The strategy should focus on interfering with the disease network rather than some individual gene and target protein. We reviewed the recent studies on the " disease-gene-target-drug" network,including the topology of network pharmacology and some methods for polypharmacology design,and analyzed some problems and challenges in these studies.
[1]KOLA I,LANDIS J.Can the pharmaceutical industry reduce attrition rates[J].Nat Rev Drug Discov,2004,3(8):711-716.
[2]BARTER PJ,CAULFIELD M,ERIKSSON M,et al.Effects of torcetrapib in patients at high risk for coronary events[J].N Engl J Med,2007,357(21):2109-2122.
[3]WAGNER BK,KITAMI T,GILBERT TJ,et al.Large-scale chemical dissection of mitochondrial function[J].Nat Biotechnol,2008,26(3):343-351.
[4]HOPKINS AL.Network pharmacology:the next paradigm in drug discovery[J].Nat Chem biol,2008,4(11):682-690.
[5]PAOLINI GV,SHAPLAND RH,van HOORN WP,et al.Global mapping of pharmacological space[J].Nat Biotechnol,2006,24(7):805-815.
[6]HOPKINS AL.Network pharmacology[J].Nat Biotechnol,2007,25(10):1110-1111.
[7]GOH KI,CUSICK ME,VALLE D,et al.The human disease network[J].PNAS,2007,104(21):8685-8690.
[8]YILDIRIM MA,GOH KI,CUSICK ME,et al.Drug-target network[J].Nat Biotechnol,2007,25(10):1119-1126.
[9]KINGSMORE SF,LINDQUIST IE,MUDGE J,et al.Genome-wide association studies:progress and potential for drug discovery and development[J].Nat Rev Drug Discov,2008,7(3):221-230.
[10]SHERRY ST,WARD MH,KHOLODOV M,et al.dbSNP:the NCBI database of genetic variation[J].Nucleic Acids Res,2001,29(1):308-311.
[11]ZAMBROWICZ BP,SANDS AT.Modeling drug action in the mouse with knockouts and RNA interference[J].Drug Discov Today:Targets,2004,3(5):198-207.
[12]DEUTSCHBAUER AM,JARAMILLO DF,PROCTOR M,et al.Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast[J].Genetics,2005,169(4):1915-1925.
[13]AUSTIN CP,BATTEY JF,BRADLEY A,et al.The knockoutmouse project[J].Nat Genet,2004,36(9):921-924.
[14]HILLENMEYER ME,FUNG E,WILDENHAIN J,et al.The chemical genomic portrait of yeast:uncovering a phenotype for all genes[J].Science,2008,320(5874):362-365.
[15]CHEN Y,ZHU J,LUM PY,et al.Variations in DNA elucidate molecular networks that cause disease[J].Nature,2008,452(7186):429-435.
[16]SCHADT EE,FRIEND SH,SHAYWITZ DA.A network view of disease and compound screening[J].Nat Rev Drug Discov,2009,8(4):287-295.
[17]RAMASWAMY S.Rational design of cancer-drug combinations[J].N Engl J Med,2007,357(3):299-300.
[18]LOGING W,HARLAND L,WILLIAMS-JONES B.High-throu-ghput electronic biology:mining information for drug discovery[J].Nat Rev Drug Discov,2007,6(3):220-230.
[19]WREN JD,BEKEREDJIAN R,STEWART JA,et al.Knowledge discovery by automated identification and ranking of implicit relationships[J].Bioinformatics,2004,20(3):389-398.
[20]JOY MP,BROCK A,INGBER DE,et al.High-betweenness proteins in the yeast protein interaction network[J].J Biomed Biotechnol,2005,2005(2):96-103.
[21]KEITH CT,BORISY AA,STOCKWEL BR.Multicomponent the-rapeutics for networked systems[J].Nat Rev Drug Discov,2005,4(1):71-78.
[22]OVERINGTON JP,AL-LAZIKANI B,HOPKINS AL.How many drug targets are there?[J].Nat Rev Drug Discov,2006,5(12):993-996.
[23]JIA J,ZHU F,MA X,et al.Mechanisms of drug combinations:interaction and network perspectives[J].Nat Rev Drug Discov,2009,8(2):111-128.
[24]MORPHY R,KAY C,RANKOVIC Z.From magic bullets to designed multiple ligands[J].Drug Discov Today,2004,9(15):641-651.
[25]DESSALEW N,WORKALEMAHU M.On the paradigm shift to-wards multitarget selective drug design[J].Curr Comput Aided Drug Des,2008,4(2):76-90.
[26]MESTRES J,GREGORI-PUIGJANE,VALVERDE S,et al.Data completeness—the Achilles heel of drug-target networks[J].Nat Biotechnol,2008,26(9):983-984.
基本信息:
中图分类号:R963
引用信息:
[1]潘家祜.基于网络药理学的药物研发新模式[J].中国新药与临床杂志,2009,28(10):721-726.
2009-10-25
2009-10-25