国外药物靶标开发的现状及特点分析

,,(,100850)[],,[];;;[]R95[]C[]1003-3734(2008)07-0621-04StatusandcharacteristicsintheexplorationofdrugtargetsabroadZHANGYin,WANGSong2jun,DIAOTian2xi(InstituteofHealthServiceandMedicalInformation,AcademyofMilitaryMedicalSciences,Beijing100850,China)[Abstract]Drugsexerttheirtherapeuticeffectbybindingandregulatingparticularproteinornucleicacidtargets.Alargenumberoftargetshavebeenexploredfordrugdiscovery.Researchfocushasbeenaimedatthesearchofnewtargetsandfurtherexplorationofexistingtargets.Knowledgeofthetargetsfacilitatestheunderstand2ingofmolecularmechanismsofdrugsandtheregularpatternsinnewdrugdevelopment.[Keywords]newdrug;drugtarget;status;characteristic,,,,2000Celera,6001800,2100siRNA[1],,,,,,,(),,,,[2],Drews[3],GoodmanGilmaPharmacologicalBasisofTherapeutics(),,1,,,,1,483(),,126ChineseJournalofNewDrugs2008,Vol.17No.72008177300015000,,HopkinsGroom5120[4]2003,Golden273[5]2006,Imming[6],,,X218Overington[7],FDA()CBER()21000(),1357,,324266,248,207;227,186,,,,,2.1Overington[7],,50%4:G2(2618%)(13%)(719%)(5.5%)DNAP450Betz[1],G2G2,,,,2.2,(60%),(16%)(10%)(8%)(3%)(2%)(1%)[8],,1/3,(OMIM),2.3Chen[9](TTD)268,,:()()[10,11];:()[12];:()[13];:()[14,15],[16],,G2,G2226ChineseJournalofNewDrugs2008,Vol.17No.72008177N2(NHRs),(),,,,2,,;,,,,,,,11[16]/2291998K2519964511995S1619941819932310199226199022141988L151976Kanehisa[17],SWISS2PORT,Kyoto(KEGG):(6),(3),(3),Zheng[16],50%,,,:5,2,2,,,,[18],,2000Celera,NI2HCM(NIHCareManagementFoundation)FDA1989-2000361,6%,,me2too,,,,,,,,,[19],326ChineseJournalofNewDrugs2008,Vol.17No.72008177,,,,,,[](1980-),,[](1966-),,,::[phone],E2mail:[e-mail][][1]BETZUA.Howmanygenomicstargetscanaportfolioafford?[J].DrugDiscovToday,2005,10(15):1057-1063.[2]COMESSKM,SCHURDAKME.Curropindrugdiscovdevel[J].CurrOpinDrugDiscovDevel,2004,7(4):411-416.[3]DREWSJ,RYSERS.Theroleofinnovationindrugdevelop2ment[J].NatBiotechnol,1997,15(13):1318-1319.[4]HOPKINSAL,GROOMCR.Thedruggablegenome[J].NatRevDrugDiscov,2002,1(9):727-730.[5]GOLDENJB.Prioritizingthehumangenome:knowledgeman2agementfordrugdiscovery[J].CurrOpinDrugDiscovDevel,2003,6(3):310-316.[6]IMMINGP,SINNINGC,MEYERA.Drugs,theirtargetsandthenatureandnumberofdrugtargets[J].NatRevDrugDiscov,2006,5(10):821-834.[7]OVERINGTONJP,AL2LAZIKANIB,HOPKINSAL.Howmanydrugtargetsarethere?[J].NatRevDrugDiscov,2006,5(12):993-996.[8]LEGALLT,ROMEROPR,CORTESEMS,etal.Intrinsicdis2orderintheProteinDataBank[J].JBiomolStructDyn,2007,24(4):325-342.[9]CHENX,JIZL,CHENYZ.TTD:therapeutictargetdatabase[J].NucleicAcidsRes,2002,30(1):412-415.[10]JUNGM,KIMH,KIMM.Chemicalgenomicsstrategyforthediscoveryofnewanticanceragents[J].CurrMedChem,2003,10(9):757-762.[11]ELSAYEDYA,SAUSVILLEEA.Selectednovelanticancertreatmentstargetingcellsignalingproteins[J].Oncologist,2001,6(6):517-537.[12]BELVISIMG,HELEDJ,BIRRELLMA.Newanti2inflammatorytherapiesandtargetsforasthmaandchronicobstructivepulmona2rydisease[J].ExpertOpinTherTargets,2004,8(4):265-285.[13]WINDISCHM,HUTTER2PAIERB,SCHREINERE.Cur2rentdrugsandfuturehopesinthetreatmentofAlzheimerpsdis2ease[J].JNeuralTransm,2002,62(Suppl1):S149-S164.[14]FRANTZS.Drugdiscovery:playingdirty[J].Nature,2005,437(7061):942-943.[15]BICKNELLKA,SURRYEL,BROOKSG.Targetingthecellcyclemachineryforthetreatmentofcardiovasculardisease[J].JPharmPharmacol,2003,55(5):571-591.[16]ZHENGC,HANL,YAPCW,etal.Progressandproblemsintheexplorationoftherapeutictargets[J].DrugDiscovToday,2006,11(9-10):412-420.[17]KANEHISAM,GOTOS,KAWASHIMAS,etal.TheKEGGresourcefordecipheringthegenome[J].NucleicAcidsRes,2004,32(Databaseissue):D277-280.[18]BOOTHB,ZEMMELR.Questforthebest[J].NatRevDrugDiscov,2003,2(10):838-841.[19]BOTTINGEREP.Foundations,promisesanduncertaintiesofpersonalizedmedicine[J].MtSinaiJMed,2007,74(1):15-21.:/:2007-11-29(620),,,,[](1972-),,,:[phone]-458,E2mail:[e-mail][][1]OCHSNERM.Photophysicalandphotobiologicalprocessesinthephotodynamictherapyoftumours[J].JPhotochemPhotobiolB,1997,39(1):1-18.[2]GOMERCJ.Preclinicalexaminationoffirstandsecondgenerationphotosensitizersusedinphotodynamictherapy[J].PhotochemPhotobiol,1991,54(6):1093-1107.[3]DOLMANSDE,FUKUMURAD,JAINRK.Photodynamicthera2pyforcancer[J].NatRevCancer,2003,3(5):380-387.[4]DOUGHERTYTJ,GOMERCJ,HENDERSONBW,etal.Photo2dynamictherapy[J].JNatlCancerInst,1998,90(12):889-905.[5]KULKAU,SCHAFFERM,SIEFERTA,etal.Photofrinasara2diosensitizerinaninvitrocellsurvivalassay[J].BiochemBiophysResCommun,2003,311(1):98-103.[6],,,.[J].2000,10:86-89.[7]MOANJ.PropertiesforoptimalPDTsensitizers[J].JPhotochemPhotobiolB,1990,5(3-4):521-524.:/:2007-09-11426ChineseJournalofNewDrugs2008,Vol.17No.72008177