冠状病毒Coronavirusl论文-2013 Discovery, Synthesis, And Structure-Based Optimization of a Series of_ _i_N__i__ -(_.pdf

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1、Articlepubs.acs.org/jmcDiscovery,Synthesis,AndStructure-BasedOptimizationofaSeriesofN‑(tert-Butyl)-2‑(N‑arylamido)-2-(pyridin-3-yl)Acetamides(ML188)asPotentNoncovalentSmallMoleculeInhibitorsoftheSevereAcuteRespiratorySyndromeCoronavirus(SARS-CoV)3CLProtease†,‡,§⊥†,‡,§†,‡,§∥JonJacobs,ValerieGrum-Tok

2、ars,YaZhou,MarkTurlington,S.AdrianSaldanha,∥▽†,‡,§▽▽PeterChase,AimeeEggler,EricS.Dawson,YahiraM.Baez-Santos,SakshiTomar,¶¶†,‡,§,#∥,▽AnnaM.Mielech,SusanC.Baker,CraigW.Lindsley,PeterHodder,AndrewMesecar,*,†,‡,§,#andShaunR.Stauffer*†DepartmentofPharmacology,VanderbiltUniversityMedicalCenter,Nashville,T

3、ennessee37232,UnitedStates‡VanderbiltCenterforNeuroscienceDrugDiscovery,VanderbiltUniversityMedicalCenter,Nashville,Tennessee37232,UnitedStates§VanderbiltSpecializedChemistryCenterforProbeDevelopment(MLPCN),Nashville,Tennessee37232,UnitedStates⊥DepartmentofMolecularPharmacologyandBiologicalChemistr

4、y,NorthwesternUniversity,Chicago,Illinois60607,UnitedStates∥LeadIdentificationDivision,TranslationalResearchInstitute,ScrippsResearchInstituteMolecularScreeningCenter,130ScrippsWay,Jupiter,Florida33458,UnitedStates▽DepartmentofBiologicalSciences,PurdueUniversity,915WestStateStreet,WestLafayette,Indi

5、ana47907,UnitedStates¶DepartmentofMicrobiologyandImmunology,LoyolaUniversityMedicalCenter,2160SouthFirstAvenue,Maywood,Illinois60153,UnitedStates#DepartmentofChemistry,VanderbiltUniversity,Nashville,Tennessee37232,UnitedStates*SSupportingInformationABSTRACT:Ahigh-throughputscreenoftheNIHmolecularli

6、brariessamplecollectionandsubsequentoptimizationofaleaddipeptide-likeseriesofsevereacuterespiratorysyndrome(SARS)mainprotease(3CLpro)inhibitorsledtotheidentificationofprobecompoundML188(16-(R),(R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-car-boxamide,Pubche

7、mCID:46897844).Unlikethemajorityofreportedcoronavirus3CLproinhibitorsthatactviacovalentmodificationoftheenzyme,16-(R)isanoncovalentSARS-CoV3CLproinhibitorwithmoderateMWandgoodenzymeandantiviralinhibitoryacti