Drug Discovery Using Chemical Systems Biology Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors 英文参考文献.docVIP

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Drug Discovery Using Chemical Systems Biology Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors 英文参考文献.doc

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Drug Discovery Using Chemical Systems Biology Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors 英文参考文献

DrugDiscoveryUsingChemicalSystemsBiology: IdentificationoftheProtein-LigandBindingNetworkTo ExplaintheSideEffectsofCETPInhibitors LiXie1,JerryLi2,LeiXie3*,PhilipE.Bourne1,3* 1SkaggsSchoolofPharmacyandPharmaceuticalSciences,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2TorreyPinesHighSchool,San Diego,California,UnitedStatesofAmerica,3SanDiegoSupercomputerCenter,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinicalindications.Weintroduceanovelcomputationalstrategytoidentifyprotein-ligandbindingprofilesonagenome- widescaleandapplyittoelucidatingthemolecularmechanismsassociatedwiththeadversedrugeffectsofCholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovasculardisease.However,clinicalstudiesindicatedthatoneCETPinhibitor,Torcetrapib,hasdeadlyoff-targeteffects asaresultofhypertension,andhenceithasbeenwithdrawnfromphaseIIIclinicaltrials.Wehaveidentifiedapanelofoff- targetsforTorcetrapibandotherCETPinhibitorsfromthehumanstructuralgenomeandmapthosetargetstobiological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes,ourfindingssuggestthatadversedrugeffectsmightbeminimizedbyfine-tuningmultipleoff-targetinteractions usingsingleormultipletherapies.Thisworkextendsthescopeofchemogenomicsapproachesandexemplifiestherolethat systemsbiologyhasinthefutureofdrugdiscovery. Citation:XieL,LiJ,XieL,BournePE(2009)DrugDiscoveryUsingChemicalSystemsBiology:IdentificationoftheProtein-LigandBindingNetworkToExplainthe SideEffectso