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1、JOURNALOFCOMPUTATIONALBIOLOGYVolume17,Number5,2010#MaryAnnLiebert,Inc.Pp.669684DOI:10.1089/cmb.2009.0032Protein-ProteinInteractionNetworkEvaluationforIdentifyingPotentialDrugTargets11*FEREYDOUNHORMOZDIARI,*RAHELEHSALARI,21VINEETBAFNA,andS.CENKSAHINALPABSTRACTAspathogensevolv
2、eeffectiveschemestoovercometheeffectofantibiotics,theprevalentonedrugandonedrugtargetapproachisfallingbehind.Weproposenovelstrategiesforidentifyingpotentialmultiple-drugtargetsinpathogenicprotein-proteininteraction(PPI)networkswiththegoalofdisruptingknownpathways/complexes.G
3、ivenasetSofpathogenicpathways/complexes,wefirstconsidercomputingtheminimumnumberofproteins(withnohumanorthologs)whoseremovalfromthePPInetworkdisruptsallpathways/complexes.Unfortunately,eventhebestapproximationalgorithmsforthis(NP-hard)problemreturntoomanytargetstobepractical.
4、Thus,wefocusoncomputingtheoptimaltradeoff(i.e.,maximumratio)betweenthenumberofdisruptedessentialpathways/complexesandtheproteintargets.Forthissparsestcutproblem,wedescribetwopolynomialtimealgorithmspffiffiffiwithrespectiveapproximationfactorsofjSjandO(n)(n:numberofnodes).OntheEsch
5、erichiacoliPPInetworkwithnineessential(signaling)pathsfromtheKEGGdatabase,ouralgorithmsshowhowtodisruptthreeofthembytargetingonlythreeproteins(twoofthemessentialproteins).Wealsoconsiderthecasewheretherearenoavailableessentialpathways/complexestoguideus.Inordertomaximizethenu
6、mberofdisruptedpotentialpathways/complexes,weshowhowtocomputethesmallestsetofproteinswhoseremovalJournalofComputationalBiology2010.17:669-684.partitionsthePPInetworkintotwoalmost-equalsizedsubnetworkssoastomaximizethenumberofpotentialpathways/complexesdisrupted.Thisapproachy
7、ields28potentialtar-gets(fourofthemknowndrugtargets)ontheE.coliPPInetworkwhoseremovalpartitionsittotwosubnetworkswithrelativesizesof15.Keywords:algorithms,biochemicalnetworks,computationalmolecularbiology.1.INTRODUCTIONWithanincreaseindrug-resistantpathogenicstrains,infectio
8、usdiseasesareontherise.Downloadedfromonline.liebertpub.combyUcsfLibraryUniv
