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intransgenictobaccochloroplasts[J].JMolBiol,2001,311(5):1001.[25]deGeusB,Dol2BosmanM,ScholtenJW,etal.AcomparisonofnaturalandrecombinantcholeratoxinBsubunitasstimulatoryfactorsinintranasalimmunization[J].Vaccine,1997,15(10):1110.[26]WuHY,RussellMichaelW.InductionofmucosalandsystemicimmuneresponsesbyintranasalimmunizationusingrecombinantcholeratoxinBsubunitasanadjuvant[J].Vaccine,1998,16(223):286.[27]LianTS,BuiTot,HoRodneyJY.FormulationofHIV2envelopeproteinwithlipidvesiclesexpressinggangliosideGM1associatedtocholeratoxinBenhancesmucosalimmuneresponses[J].Vac2cine,1999,18(728):604.(:2002211207),3(,200032):,,,:;;;:R914:A:1001-2494(2003)12-0900-04:(2003):,,,Tel:(021)542370393:,,,Tel:(021)54237563E2mail:Pxia@shmu.edu.cn,(leadcompounds)[1],,(highthrough2putscreening,HTS),,,(highthroughputor2ganicsynthesis,HTOS),,,,,,,[2],2(mix2split),[34],1990,,[56][79],HTOSHTS19921998,46,[7],1(randomscreening)HTS,,,,HTSMerck25,HIV[10],1,IC50=0.17molL-1,CIC95=9.6molL-1(CIC9595%cellcultureinhibitoryconcentrations),DNADNA,(SAR),2(CIC95=0.100.62molL-1)1100,Indinavir(CIC95=0.05molL-1),50molL-1[11]SmithKlineBeecham52HT6,3,52HT650(1052HT)50,(52HT650200)009ChinPharmJ,2003December,Vol.38No.122003123812(80%)52HT64(SB2271046),,[12],5(SB2357134)52HT6,,,[13]RocheP(serumamyloidP,SAP)Alzheimer,,6(Ro1523479,IC50=100molL-1)7(Ro6322346,IC50=50molL-1),68(Ro6323300,IC50=5molL-1),89(Ro6328695,IC50=0.9molL-1),SAP,SAP,SAP,9Alzheimer[14]191119,,2(thematiclibraries)(naturalproducts)(privilegedscaffolds)(fragmentsofproteinsurfaces)(proteinsurfacemimetics),:,,Boger(Stallimycin,DistamycinA),3,2640[15],(10,IC50=42molL-1)1000DNA11(IC50=29nmolL-1)CuracinA(IC50=520nmolL-1),(),WipfCuracinA,,12,1213,IC50=170nmolL-1,CuracinA[16]1013221013,,,,3(focusedscreening),,,,,(SAR),,,,,1092003123812ChinPharmJ,2003December,Vol.38No.12FTI2276(14),Abbott,[17],,15,IC50=0.20nmolL-1,EC50=4.4nmolL-1,RWJohnson16(RWJ250042)(I),,,17(RWJ253308),II[18]OntogenP2(Pgp),18(OC1442093)[19],Glaxo2SmithKline10000,PPAR(peroxisomeproliferator2activatedreceptors)19(GW8547),,20(GW501516)PPAR,X[18]HTS,,[20]14203314204(virtualsynthesis)(virtualscreening)(virtuallibrary,VL),,,VL,2VL,,,,,,VL,,,,,,;,,,Pang[21]Wang[22](3D2databasepharmacophoresearching),(DAT)21(Ki=492nm,Ki=360nm),22(Ki=11nm,Ki=11nm),2122442122,,:Lipinski[23](WDI),5,:500,logP5,5,NO()10,,:,(neuralnetworks)(deci2siontreeapproach)Ghose(Ghosesfittingapproach)[24],10%20%[25],209ChinPharmJ,2003December,Vol.38No.122003123812,[26]5,,,,(HTS),,HTS,,,;;,,,,,,,,,,,[1],,.[A].:[M].:,2001:98106.[2],.[M].:,1999:4.[3].[A].:,.[M].:,2002:178187.[4],,.[J].(),2000,36:275.[5],,.[A].:,.[M].:,2002:99129.[6].[A].:,.[M].:,1999:1517.[7]DolleRE.Comprehensivesurveyofcombinatoriallibrarysynthe2sis:1999[J].JCombChem,2000,2:383.[8]OwensJ,HindeA,RamsterB,etal.Newsinbrief/miscella2neous2firstHTSdrugcandidatesreachclinicaltrials[J].DrugDiscovToday,2001,6:230.[9]GolebiowskiA,KlopfensteinSR,PortlockDE.Leadcompoundsdiscoveredfromlibraries[J].CurrOpinChemBiol,2001,5:273.[10]HazudaDJ,FelockP,WitmerM,etal.Inhibitorsofstrandtrans2ferthatpreventintegrationandinhibitHIV21replicationincells[J].Science,2000,287:646.[11]WaiJS,EgbertsonMS,PayneLS,etal.42Aryl22,42dioxobu2tanoicacidinhibitorsofHIV21integraseandviralreplicationincells[J].JMedChem,2000,43:4923.[12]BromidgeSM,BrownAM,ClarkeSE,etal.52Chloro2N2(42methoxy232piperazin212yl2phenyl)232methyl222benzothiophe2ne2sulfonamide(SB2271046):apotent,selective,andorallybioavail2able52HT6receptorantagonist[J].JMedChem,1999,42:202.[13]BromidgeSM,ClarkeSE,GagerT,etal.Phenylbenzenesulfona2midesarenovelandselective52HT6antagonists:identificationofN2(2,52dibromo232fluorophenyl)242methoxy232piperazin212yl2benzenesulfonamide(SB2357134)[J].BioorgMedChemLett,2001,11:55.[14]PepysMB,HerbertJ,HutchinsonWL,etal.Targetedpharma2cologicaldepletionofserumamyloidPcomponentfortreatmentofhumanamyloidosis[J].Nature,2002,417:254.[15]BogerDL,FinkBE,HedrickMP.TotalsynthesisofdistamycinAand2640analogues:asolution2phasecombinatorialapproachtothediscoveryofnew,bioactiveDNAbindingagentsanddevelop2mentofarapid,high2throughputscreenfordeterminingrelativeDNAbindingaffinityorDNAbindingsequenceselectivity[J].JAmChemSoc,2000,122:6382.[16]WipfP,ReevesJT,BalachandranR,etal.Synthesisandbiologi2calevaluationofstructurallyhighlymodifiedanaloguesofthean2timitoticnaturalproductcuracinA[J].JMedChem,2002,45:1901.[17]HenryKJJr,WasicakJ,TaskerAS,etal.Discoveryofaseriesofcyclohexylethylamine2containingproteinfarnesyltransferasein2hibitorsexhibitingpotentcellularactivity[J].JMedChem,1999,42:4844.[18]HoekstraWJ,MaryanoffBE,DamianoBP,etal.Potent,orallyactiveGPIIb/IIIaantagonistscontaininganipecoticacidsubunit.Structure2activitystudiesleadingtothediscoveryofRWJ253308[J].JMedChem,1999,42:5254.[19]ZhangC,SarsharS,MoranEJ,etal.2,4,52Trisubstitutedimi2dazoles:novelnontoxicmodulatorsofP2glycoproteinmediatedmultidrugresistance.Part2[J].BioorgMedChemLett,2000,10:2603.[20]BormanS.Combinatorialchemistry[J].ChemEngNews,2002,11:43.[21]PerolaE,XuK,KollmeyerTM,etal.Successfulvirtualscreen2ingofache