2D-QSAR和HQSAR研究6-O-芳基酮内酯衍生物的定量构效关系

JournalofChinaPharmaceuticalUniversity2010,41(3):208-2152D2QSARHQSAR62O21,23,133,1,1,1(1;2,210009)3,,,62O2,(2D2QSAR)(HQSAR),492D2QSARHQSARr20184901975,q20180301926(r20178201878);;2D2QSAR;HQSAR;R914;O641A1000-5048(2010)03-0208-082D2QSARandHQSARstudyonquantitativestructure2activityrelationshipof62O2arylketolidesderivativesZOULi2yun1,CHENYa2dong23,YOUQi2dong133,ZHANGYuan1,YANGYan1,LIXiang11DepartmentofMedicinalChemistry;2DepartmentofInorganicChemistry,ChinaPharmaceuticalUniversity,Nanjing210009,ChinaAbstractAsthethird2generationantibacterialmacrolides,ketolidesnotonlyhavegoodactivityagainstdrug2re2sistantstrains,butalsoovercometheinductionofresistancetodrugs,andhavebecomethefocusintheinvestiga2tionofthemacrolides1The2D2QSAR(22dimensionalquantitativestructure2activityrelationships)andHQSAR(hologramQSAR)wereusedtodevelopQSARmodelswithatrainingsetof4962O2arylketolidederivatives1Both2D2QSARandHQSARmodelsyieldedgoodresults,includinghighconventionalcorrelation(r2)coefficients(01849,01975)andacross2validated(q2)coefficients(01803,01926)1Bothofthemodelswerevalidatedbyanexternaltestsetof9compounds,whichgaveasatisfactorypredictiver2of01782and01878,respectively1Thisstudymightprovideinsightsintofurtherstructuraloptimizationofmacrolides1Keywordsmacrolides;ketolides;2D2QSAR;HQSAR;quantitativestructure2activityrelationship(QSAR)ThisstudywassupportedbyChinaNationalKeyHi2TechInnovationProjectfortheR&DofNovelDrugs(No12008ZX094012001,No12009ZX095012003),1,[1],2[2],[3],3,14C23[1],802320102012053Tel:[phone]E2mail:ydchen@cpu1edu1cn33Tel:[phone]E2mail:youqd@cpu1edu1cn(No12008ZX094012001,No12009ZX095012003)3:2D2QSARHQSAR62O2,(telithro2mycin)[4](cethromycin)[5],,[6-8],(2D2QSAR)(hologramQSAR,HQSAR),62O2,,111[9-10],58,MIC(mol/L)pMIC(-lgMIC),,49,9,1Table1Structureandactivity(pMIC)of62O2arylketolidesderivativesCompd1CommonstructureR1R2pMICCompd1CommonstructureR1R2R3pMIC13a5163930f6118523a5195531f611853b3199232f518844b4194733f611855b4196534f614866b41968353f61486902JournalofChinaPharmaceuticalUniversity41(Continued)Compd1CommonstructureR1R2pMICCompd1CommonstructureR1R2R3pMIC73b5187036f614868b4134937f614879b3169338f61487103b41659393f6148711b4136740f6148712b4135941f5188513b4168942f6118614c5190343f5188515dH5121444f6118616dCH34132345f6149417d4136046f5186418dOCH36120247f5187319dCH36119348f51881203e4193049f51599213e6150050f6119522f6115551gHH612910123:2D2QSARHQSAR62O2(Continued)Compd1CommonstructureR1R2pMICCompd1CommonstructureR1R2R3pMIC23f6115652gHH6162024f6149053gHCH36125925f6149054gHCH36159026f6117955gHCH361909273f6118556gFCH36191928f6118557gHCH37130329f5188458gHCH3713043Testsetcompound1122D2QSAR112112DChemDraw,TSAR313,CORINA2D3D,Charge22,Cosmic,4118610-24118610-7J/mol,44112122D2QSARTSAR313,F2to2en2terF2to2leave4,(leave2one2out,LOO),44,TSAR313,017,,113HQSAR11311LinuxSYBYL713,,Sketch,Gasteiger2Hckel,HQSAR,,HQSAR,[11](47),16,2,112JournalofChinaPharmaceuticalUniversity41Table2ResultsofHQSARanalysiswithdifferentfragmentdistinctions(defaultfragment2size427)Fragmentr2cvSEPr2ncvSEEHLnA/B018890130801965011732576A/B/C019070127901974011483535A/B/C/H01897012980196401176596A/B/C/H/Ch01870013310195301198715A/B/H/Ch/DA018520135301950012063535A/B/H019060128401968011653536A/B/C/Ch018830130901956011903074A/B/DA018310137201933012343534A/B/C/DA018720133201976011451516A/B/H/DA018700133501970011603536A/B/C/Ch/DA01853013520194901207595A/B/C/H/DA017930141701959011852575A/B/C/H/Ch/DA01795014200195301201836A/C/H/DA01840013630192001256834A/C/Ch/DA018390135901904012782573A/C/DA018360137101944012173535A:atoms;B:bonds;C:connections;H:hydrogenatoms;Ch:chirality;DA:donor&acceptorSEP:Standarderrorofpredict;SEE:Standarderrorofestimate;HL:hologramlength;n:optimalnumberofcomponents113125340112:535961718397151199257307353401,1211313,,[12](47),,,3Table3HQSARanalysiswithdifferentfragmentsizes(fragmentdistinctionA/B/C)Fragmentsizer2cvSEPr2ncvSEEHLn225019260125301975011471516326019220125501974011471515427019070127901974011483535528018740132201956011911514629018650133301947012094014721001849013520193501232401482110184801354019300124040142112D2QSAR,(1)pMIC=7181710-5X1+010945X2+010202X3-11877X4+71324(1)n=49,r=01922,r2=01849,q2=01803,s=01352,F=611989X1:,X2:,X3:Lipole,X4:BalabanQSARr2q2QSAR:r21,QSAR,QSARr2016[13](1)r201849(016),8419%q2,q2QSAR,QSARq2015[13]q201803,,s013523,,,r201782,2123:2D2QSARHQSAR62O2584,1(A,B)Table4Observedandpredictedactivitiesofcompoundsusing2D2QSARHQSARmodelsCompd1pMIC2D2QSARPred1Resi1HQSARPred1Resi1Compd1pMIC2D2QSARPred1Resi1HQSARPred1Resi1135163951222014175152301116306118561307-01122611710101423519555158801367518350112031611856111801067611270105833199231601013913185101141325188461194-0131061198-0131444194741792011554180201145336118561385-0120061353-011685419654171301252418940107134614866107101415613820110464196841975-0100741887010813536148661427010596140901077735187051670012005111401756366148661549-01063614120107484134941872-0152341642-01293376148761651-011646141501072931693315960109731791-01098386148761395010926132701161034165941671-01012415220113739361