手性物质的QSAR研究及环境学意义

:200811,:20092*(No.20777035,20737001)(863)(No.2007AA06Z416,2006AA06Z424)(No.20070284021)**Correspondingauthoremail:[e-mail]手性物质的QSAR研究及环境学意义*穆云松刘磊张爱茜**蔺远王连生(南京大学环境学院污染控制与资源化研究国家重点实验室南京210093)本文综述了近年来应用定量结构活性相关(QSAR)方法研究化学品手性问题的最新进展,重点关注了不同QSAR方法对于手性分子空间特异性的表征,包括传统二维QSAR方法分子全息方法(HQSAR)手性拓扑指数法(CTI)和比较分子场分析法(CoMFA)除此之外,简要介绍了国内外对环境污染物对映体效应差异的研究进展及已有工作基础,并对QSAR方法应用于手性环境污染物的研究前景进行了展望手性定量结构活性相关对映体选择环境污染物:X131:A:1005281X(2009)10223507QSARStudyonChiralChemicalsandFurtherApplicationinEnvironmentalScienceMuYunsongLiuLeiZhangAiqian**LinYuanWangLiansheng(StateKeyLaboratoryofPollutionControlandResourceReuse,SchooloftheEnvironment,NanjingUniversity,Nanjing210093,China)AbstractInthispaper,thecurrentprogressofquantitativestructureactivityrelationships(QSAR)studyisreviewedinthefieldofinvestigatingchiralchemicals.DifferentQSARmethods,fromtwodimensionstothreeones,adoptvariouschiraldescriptorstodistinguishtwoenantiomersintheevaluationoftheirstereospecificprocess.Theclassical2DQSAR,HQSAR,chiraltopologicalindex(CTI)andCoMFAhavebeenintroduced,focusingonhowtointerprettheasymmetryofchiralchemicals.Furthermore,studiesontheenantioselectivebehaviorofchiralcontaminantsinrecentdecadearealsopresented.Finally,theoutlookofQSARstudiesonchiralenvironmentalcontaminantsisproposedbutwithachallengethatmoreattentionshouldbepaidtoadvancedapplicationofchiralQSAR.Keywordschirality;QSAR;enantioselectivity;environmentalcontaminantsContents1Introduction2ApplicationofQSARinthefieldofinvestigatingchiralchemicalswithenantiospecificity2.1Classical2DQSAR2.2HolographicQSAR(HQSAR)2.3QSARbasedonchiraltopologicalindex(CTI)2.4Comparativemolecularfieldanalysis(CoMFA)3Researchprogressonchiralcontaminantsinenvironmentalprocess4Availableresearchprogress4.1HQSARstudyonchiralorganophosphoruspesticide4.2CoMFAstudyonchiralorganophosphoruspesticide5Challengeandoutlook6Conclusion2110200910化学进展PROGRESSINCHEMISTRYVol.21No.10Oct.,20091,,10050(FDA),,,,,[13],,:,(chiralswitching)[4][5],,[6],,,,,,,(QSARQSPR),2060Hansch,,1890,Guye,,,QSAR,2QSARQSAR,,QSAR,,,,QSAR,2.1QSAR,QSAR,QSARAndrisano[7,8](HPLC)2,33QSAR(CD),HAS,(logKow)(),,,,KoWon[9]QSAR30IC50Cerius(MolecularSimulations,SanDiego,CA,USA)QSAR+78,,5RS,,,Chilmonczyk[10]QSAR,,,2.2HQSAR2236化学进展21HQSAR(holographicQSAR,HQSAR),,,,[11]HQSAR3,5(CDMPC),,12,atoms+bonds+connections+hydrogenatoms+chirality,HQSARq20.797(logk1)0.541(logk2),q20.824(logk1)0.731(logk2),Nair[12]CCR21logk1[11]Fig.1Fitgraphofcomputedpredictedvaluesvsobservedvaluesofazoleantifungalagents[11]2logk1[11]Fig.2Fitgraphofcomputedpredictedvaluesvsobservedvaluesoforganicphosphonateagents[11],,S2.3QSAR(Am)QSAR,,,,,,[13],1998,deJulinOrtiz[14],(3)D2[15,16],,,QSAR:log(1IC50)=-3.72(!0.96)+0.54(!0.09)eAm3-3.59(!1.79)∀e3p+8.94(!2.99)∀e5pR=0.983,S=0.22,F=92.60,N=14(1)(1)Am,,09650983,QSARMarreroPonce[17,18]#∃,,QSAR,,(q2=0912,scv=0289q2=0957,scv=0211),CastilloGarit[19,20]GonzlezDaz[21]QSAR,,3Dchiral(25)TOMOCOMDCARDD,QSAR[22],223710QSAR,Golbraikh[23,24]EZRS,(CTIs)24(CoMFA)Pirkle[25],CoMFA,CoMFACoMFAsp3,Schefzick[26]QSAR,CoMFA,,CoMFA,[27],[28][29]CoMFADelRio[30],143WhelkO1HPLC3,compoundselectioncorinagridcalculationtransformationdataanalysis3[30]Fig.3Calculationschemeofgridbaseddescriptors[30]4,q2=085,WhelkO1,4[30]Fig.4Plotofpredictedvsexperimentalenantioselectivities[30]Dervarics[31],,(chiralitysensitiveflexibility,CSF)5,,,3738PGF2!,5(CSF)[31]Fig.5SchematicdefinitionofthepointplanedistancefortheCSFdescriptor[31]CoMFA[32],,#∃,[32],[3335]CoMFA,CoMFA[3638]2238化学进展2132090,Kohler[39]Williams[40]25%,Lewis[41]Williams,,,,[41],DDT[42],,,,[42]10,,,,,,,441HQSARHQSAR,,[42]HQSAR23,HQSAR(GCRI)[43]TriposSYBYL7323,HQSAR(),()PLS,GCRI,36[44]1,Ch,RSq2LOO,Ch,q2LOO,HQSAR,,HQSAR,1ChHQSARTable1Influenceofchiralfragmentparameter(Ch)toHQSARmodelcompoundfragmentparametersq2LOOSELOO23RA+B+Co+H+DA077298775A+B+Co+Ch+H+DA072610241223SA+B+Co+H+DA077298775A+B+Co+Ch+H+DA075510234123R+23SA+B+Co+H+DA099119652A+B+Co+Ch+H+DA099317684q2LOO,leaveoneoutcrossvalidatedcorrelationcoefficient;SELOO,leaveoneoutcrossvalidatedstandarderror;A,atoms;B,bonds;Co,connections;H,hydrogenatom;Ch,chirality;DandA,donorandacceptor42CoMFACoMFA3DQSAR[45,46]HQSAR,,CoMFA,(RS)CoMFA,,21,,TriposCoMFA,q2=0947r2=0993,6,223910QSAR6,CoMFA,CoMFA,,,,6(SR)CoMFAFig.6CoMFAcontourofchiralorganophosphorusenantiomers5,,,QSAR,,QSAR:(1)QSAR,,(2),(3),,,,,QSAR,,,,6QSAR,QSARQSARHQSAR,,QSAR,,,,QSAR,,,,,QSAR,QSAR,[1]HuttAG,O%GradyJ.J.Antimicrob.Chemother.,1996,37:732[2]TannerME.Acc.Chem.Res.,2002,35:237246[3]ReddyA,HashimM,WangZ,etal.Int.J.Pharm.,2007,335(12):6369[4]TuckerGT.TheLancet,2000,355:10851087[5]AgranatI,CanerH,CaldwellJ.NatureReviewsDrugDiscovery,2002,1:753768[6]BauerA,WestkmperF,GrimmeS,etal.Nature,2005,436:11391140[7]AndrisanoV,BertucciC,CavriniV,etal.J.Chromatogr.A,2000,876(12):7586[8]AndrisanoV,GottiR,RecanatiniM,etal.J.Chromatogr.B,2002,768(1):137145[9]KoK,WonY.Bioorg.Med.Chem.,2005,13(5):14451452[10]ChilmonczykZ,Ksyci!skaH,Po∀e'c.J.Chromatogr.B,1998,720(12):6569[11](WangHQ),(HuGX),(YuQS),(ZouJW).()(JournalofZhejiangUniversity(ScienceEdition)),20