Systematic Identification of Scaffolds Representing Different Types of Structure-Activity Relationships [Elektronische Ressource] / Ye Hu

Ye Hu

Sujets

• Biologie
• Gesundheit

Informations

• Publié par: rheinische_friedrich-wilhelms-universitat_bonn
• Publié le: 01 janvier 2011
• Nombre de lectures: 14
• Langue: English
• Poids de l'ouvrage: 13 Mo

Extrait

h-NaturwissenscSystematicoIdenRheiniscticationausofakSh-Wilhelms-UnivcaoldsonRepresenMarctinghenDierenlt?ttFTBonnypgelegtesHofChinaStructure-A2011ctivithaftlicyFRelationshipsuKumderulativheneriedricDissertationersit?tzurvErlangungrdesvDoktorgradesYe(Dr.ureJiangsu,r.Bonnnat.)h,derMathematiscDr.Angefertigtnat.mitt:Genehmigung2.derhaelMathematiscDr.h-NaturwissenscBahaftlict:henat.Fhoakult?tUniv.-Prof.derrer.RheiniscJ?rgenhenjorathFReferenriedricUniv.-Prof.h-Wilhelms-Univrer.ersit?tMicBonnG?tsc1.wReferenofAbstractyIncomedicinalsharecehemistrypromiscuous.,,itatisselectivofthecenagainsttraloundimpindiviortanceetowith,understandastructure-isactivitlatedyvrelationshipsscaolds(SARs)corre-ofandsmallpairwisebioactivyeaddition,compeounds.areTinypicallyrelationships,activitSARsidenareectivitanalyzedactivonthataunitiescase-bty-caseonebasisidenforromiseEightscofcompcompdierenoundsconsideredactivbeyagainsttheaformgivyenptarget.targetsHoectivwetevscaoldser,foundtheinincreasingwithamounto,tsubstructureofocompstagesoundFactivitaticyproledatadomaithatcompisout.bcompecomingforacloselyvandailableoundsallofwstargetSARsotherstoInbofeyexploredthoroughlyony-threeaeringlarge-scypale.ondMoreoactivvleaster,targetmolecularusscaoldsbderivvedinfromfoldbioactivceotencycompensioundsscaoldsareulti-targetalsoselofand,highglobalintialterestaforquanSARassessed,analysis..Irelationshipsneengeneral,explored.scaoldsfromareoundsobtainedbbolvyrelationshipsremoologicalvingTheseallalsosubcomstihi-ttoueprediction.nccurtscertainfromareringstied.andurthermore,fromsystem-linkselersybanalysisetpublicwneenerings.oundsThiscarriedthesisScaoldsaimsyieldatoundssystematiceallycommminingofcompre-oundstargetsforrepresenwhiccomphselectivactivitonlyyoran-particularnotationsoareeraarevtied.ailableaddition,anddegreeinpvscuitestigatingofrelationshipsisbexamined.ettwscaoldseenvc33hemicalhemotstruc-esturespandtobiologicaloundsactivitieseatatthethreelevtelfamiliesofthactivareetocompeounds,Moreoiner,particular,ymoleculartegratingscaolds.scaf-Therefore,similaritdataandminingompapproacphesdierences,arepropdesignedttoofiden-totifymscaoldsactivitwithordierenectivittclisstructuralinand/ortheactivitscaoldyotencofharacteristics.duInitiallyl,arescaoldtitativdistributionslyinrespcompelyoundsFinallyatstructuraldierenbtwstagesscaoldsofsystematicallypharmaceuticalMostde-extractedvactivelopmencomptarearetoanalyzed.eSevtedssubstructureofand/orscaoldstopthatfeaturesoothers.vsubstructureerlaparebcomparedetandwbinedeenhierarcdierencaltrelationshipsstagesfacilitateorypreferentiallyBatista,AycmknoewledgmenttstIawmanouldWlikIefortoforrstthethankmmatmosphere.ygivsupPervisorIyProf.fruitfulDr.eJ?rgeneciallBaofjoratheforecialhisrinspirationalearsguidance,eengreatabpatienceork-,eciallyconthankstintouousLounkine,suppAnneortandandforencouragemenorationstFinallyduringouldmthankyfriends,PhDQiongstudyy.andIhawerouldandalsotoliforkortefewtoIthankeProf.GeDr.yMicorativhaelwG?tscinghoEspw,forybareeeningJos?co-referenEugentLisaandeltason,takingMaitimeassermanntoPreetirevieerwpleasanmcollabyandthesis.discussions.I,wwouldlikliktoealltoyexpressespmyyLin,gratitudeantokindallhelpmencouragemenytheycolleaguesvofevthedoneLSImeresearcsphthanksgroupmforfamilyprotheividingsupptheduringhepastlpful,yfriendlysince,hinvteractivbeinarnand.collyConCompten.ts.In.tro.duction.1.1.Scaold.Distributions.in.Bioactivductione.Molecules,.Clinical.T.rials51Comp.ounds.and.DrugsSummary9.In.troofduction............Molecular.ctivit.............................P.ing:.es................9SummaryPublication........P.orm.51....................................................11.Summary..37.Direct.Data.ti-.Chemot.In.................Publication.................................49.with15op2oSystematicargetAnalysisClioftroPublic.Domain.C.o.mp.ound.P.otency.Data.Iden.ties.Selectiv.e.Molecular.S.caolds.A53cross.D.ruggab.le.T.ar-.get.F.amiliesi17.In.tro.duction....................31...................................4.olypharmacology.ed.ound.Min17IdenPublicationcation.Promiscuous.yp.39.tro.................................39......................19.Summary........41...................................5.Scaolds.High.r.ensit.t.F.Multi-T.A.y.s.In27duction3.Exploring.T.arget-Selectivit.y.P.atterns.of.Molecular.Scaolds.29.In.tro.duction......Publication.................................Summary........................29.Publication......65..856.Global.Assessmen.t.of.Scaold.Hopping.PAoten.tial.for.Curren.t.Pharmaceutical.T.argetsertical67.In.tro87duction........................Horizon.Scaold.87....................................67.Publication..Summary.................Com.and.Relationships.hies.y.tro.................................8969.Summary..............Conlcusion.............................79......................75.7.Structural.and.P.otency.Rela8tbiningiontalshipsVBetSubstructurewineenHierarcScaoldsforofctivitCPredictionomIn-ductionp.ounds.A.ctiv.e.Again.st.Human.T.a.r.gets.77.In.tro.duction..Publication.................................Summary............................77.Publication..99.101.
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sevcompletiontofotencyhailumanquangenomevprohijecd-tor,eitAhasebSAReenerpredictedsthatlearningproalsod-umeri-uctsaddition,ofgraphicallyAfterounds3,000dierengeneshmighetcanrepresentarget.tadruggablehestargetssucandtitativduction[6]600Recetodologiestroe1,500eofbthesesettargetslandscapmighentothbtebiologicaldirectlylandscaplinkcedintoo-dimensionaldiseases[11][1,regions2].calOnnthesubstitu-otherorhand,purpcumhemicalcomputationalspaceaconsistinglofasallcalpSARossible[5],smallmacmoleculeshniquesistlyestimatednewtovconeentained.moredithantthefunctionsvIndesignedharacterizeelytainedfeaturesmoleculesawith9].atactivitmostha30bheadvytatomsand[3].bHoeenwvingevyer,tivitbio-slogicallydesignrelevyanbtducedcthemicalwspaceythatthree-dimensionalconsists[12],ofyingcandhemicalccompeouFndstributionsactingenonFbiologicaltsystemsrepresenose,tsnonlybaofsmallapproacfractionareofvtabheeoreticallyhpclaossiblesicquanhemicalespacemo[4].elsInpharmacophorecorhemicalhinebiologytecand[7].medicinalnc,hemistryeralresearcmethoh,haiteisbofdevhighlopimpFortance,example,andalsorencnhallcalenging,hatoeuneendetortitativstandcstructure-activitSARyconrelationshipsin(SARs)dataof[8,sucInhcomputationalbioactivyeescompvoundsalsothatebindutilizetotoonerepresenorbmorestructureindividualptargetsrelationshipsandetriggerwbiologiccompalharespsimilaronsesactivitand[10].therapc-euticyeects.eStructure-AofctivittyandRelationshipomplexitshaTeraditionalleenytro,sucSARsashawvNeteork-likbSimilariteenGraphsexploredoronlandscapaviewscase-bwherey-casedisplabasis,diereni.e.globalforloindivid-SARualharacteristicscompboundideseriestied.activurthermore,econagainstofa1givde-tiontrositesproaoundsnscaolddhierarctheirxclusivcomFbinationsohasourcesvhase[25,alsovbofeentquanaromatictitativtheelytanalyzedefordatabasesseriescandidatesofscaoldsanalogousofcompprivileounds[27],[13].thoughHoecicwanevaer,2sucbhandSARwdeterminandierentsropcan19].alsoersitbforescreeningexploredoundsatandthealevtroelativoffacilitatesmoleculartscaolds.er,MolecularesScaoldsEvMolecularescaoldslegedortiallyframewbindorksAextractedDatafromscreeningaceectivtivaneTherefore,comp[16,oundsthehawvcouneompbelopabiliteen,analyzedandscphonhemicaltinandueestovbande,haoeenfthighhin[20],terestorganicinnatme[22,dicinalorcInhemistrysc.eenDierenthatttheirdenitionssofsscaoldsidenarelig-aevMoreoailable.notionFdooriginallyrbexample,etscaoldshighlymighdrugt.bareetogeneratedorbyyabreakingfamilypredenedailabilitbCompondstheinofcomphniques,oundsbonatheedbasisyoftsretrosynntheticologiesrules17].[14].urthermore,Al-relationshipternativetelyeen,ringscaoldstmighctoundalsovbyeasobtainedonbbasiyofremotvingysicalclpsubstituenertiestsringfyprom[18,ringsMoreoander,fromdistributionslinkdiversybvetbwexaminedeendierenrings,dataformingsucmolecularasframewlibrariesorks,largealsoofcalledcompBemis-Murc[21],kuraloductsscaolds23],[15].drugsAdrugn[24].umaddition,bclassicationerhemeofbscaoldinanalysesducedhaorganizesvandederivbeeeninchiearranditheedticationoutnewfromandratherypdierenst26].pvointhetsofofgevisubstructurew.,Finorducedexample,ypansossiblealscaoldistopattractivologiesforhadiscoveryePrivi-bsubstructureseenscaoldsexhaus-ttivpreferenely,eneumeratedelfor,uptotospeightargett[2830].ringsvandythePublicstructuraloundcomplexitWithyadvoftchigh-throughputhemtec-compicalcandatabasesewelyasssanalyzyedagainstonarrathofeargebasis[31].ofincreasingtheseum-scaoldtopidenbcersearly-ofanalysisactivAnalysiseyieldingcompOutlineoundsofbandecometacomverailable,ChapterwhicdohcompenablevSARswithtoofbdierenethatanalyzedIonChapteraselectivlarge).scale,activinsteadofofgoalbbypubliclyconatvseriesendtionalsccaAst.edividual-biny-casephar-inscvtiallyestigations.ChapterEortsscaoldshacloselyvIdenearebparticulareenothersdedicatedfortorepresenbuildultiplepubliclymoaccessiactivities.blemadatabasesmthatstudiesarethecompSARsosedvofdatcomplevoundsscaolds.annotatedstudieswithbtargetssignedandsetsmeasuredobindingtanities.cFconordissertationex-tample,hapters:PubChemscaold[32]oundsisstagesadevpioneeringexplorationinitiativoetthatccurhlate-stagea).sticationorganizedemillionsunitiesoftargetscomp).oundofstructuresoundsandasubforstanceoinformation.orFChapterurthermore,Searcitscaoldsalsoypconcomptainsagainstmorefamiliesthan).490,000delbioassabiologicalysThesisinclTheudjoriofngyhigh-throughputctoralscreeninghasdata.eenInsystematicaddi-oftion,inBindingDBacurrenailabletlyoundstoresa284,206thesmaelllmolecularmoleAculesofwihateheen648,915ebindingtorecordstifyforof5,662adierenldstdierenproteinStargetsR[33],haracteristicsandinformationChEMBLtendbThisdepconsistsositseigh658,075in-compcounds(a)withofmoredistributionsthancomp3,000,000atactivittyofmeasuremenmaceuticaltselopmenagainstand8,of091atar-ldsgetsmigh[34].preferenTheseodatabasesatgroand/orw(steadily1.(b)Therefore,dentheofdesignselectivofforeectivmeofcomputationalrelatedmetho(ds2for(c)miningticationlargescaoldsdatabasescompandthatextractingalwaysveailableaSARtargetinformationvboneecomesmo