Drug Discovery Using Chemical Systems Biology Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis 英文参考文献.docVIP

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Drug Discovery Using Chemical Systems Biology Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis 英文参考文献.doc

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Drug Discovery Using Chemical Systems Biology Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis 英文参考文献

DrugDiscoveryUsingChemicalSystemsBiology: RepositioningtheSafeMedicineComtantoTreatMulti- DrugandExtensivelyDrugResistantTuberculosis SarahL.Kinnings1¤.,NinaLiu2.,NancyBuchmeier3.,PeterJ.Tonge2,LeiXie4*,PhilipE.Bourne4,5* 1DepartmentofBiology,UniversityofYork,York,UnitedKingdom,2InstituteofChemicalBiologyDrugDiscovery,DepartmentofChemistry,StonyBrookUniversity, StonyBrook,NewYork,UnitedStatesofAmerica,3DepartmentofChemistryandBiochemistry,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesof America, 4San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America, 5Skaggs School of Pharmacy and PharmaceuticalSciences,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrializednations,posesagreatthreattohumanhealthanddefinesaneedtodevelopnew,effectiveandinexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticalsonaproteome-widescale.Inthispaperwefurtherdemonstratethevalueofthisapproachthroughthe discoverythatexistingcommerciallyavailabledrugs,prescribedforthetreatmentofParkinson’sdisease,havethepotential totreatMDRandXDRtuberculosis.Thesedrugs,entacaponeandtolcapone,arepredictedtobindtotheenzymeInhAand directlyinhibitsubstratebinding.ThepredictionisvalidatedbyinvitroandInhAkineticassaysusingtabletsofComtan, whose active component is entacapone. The minimal inhibition concentration (MIC ) of entacapone for Mycobacterium 99 tuberculosis (M.tuberculosis) is approximately 260.0mM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80mM. Thus the active component in Comtan repre