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:200412,:200573e2mail:zlli2662@163.com1111,23(11()400044;21400044)(MDQSAR),,MDQSAR,MDQSAR,:R914:A:10052281X(2006)0120120208ModelingTechniquesofMultidimensionalQuantitativeStructure2ActivityRelationshipinComputer2AidedDrugDesignLiangGuizhao1MeiHu1ZhouYuan1LiZhiliang1,23(11KeyLaboratoryofBiomechanicsandTissueEngineering,MinistryofEducation(ChongqingUniversity,Chongqing400044,China);21CollegeofChemistryandChemicalEngineering,Chongqing400044,China)AbstractMultidimensionalquantitativestructure2activityrelationship(MDQSAR)hasbeensuccessfullyappliedasacrucialtechniqueforcomputer2aideddrugdesign(CADD)invariousfields.Basedonplentifulliteratures,differentstrategiesandvariousmethodologiesofMDQSARaresystematicallysummarizedbycombiningwithresearchworksinauthorsplaboratory.RecentprogressofMDQSARinCADDisreviewed.Keywordsmultidimensionalquantitativestructure2activityrelationship(MDQSAR);computer2aideddrugdesign(CADD);molecularmodelingandoptimization1FisherLockandKey110,,,,40%[1,2]:;()[3],(computer2aideddrugdesign,CADD),CADD[47]CADD,,(multidimensionalquantitativestructure2activityrelationship,MDQSAR)CADD[4]MDQSAR[8,9]MDQSARADMET(adsorption,distribution,metabolism,elimination,andtoxicity)18120061PROGRESSINCHEMISTRYVol.18No.1Jan.,2006MDQSAR,(black2box),,MDQSAR,[10],MDQSARCADD2MDQSAR,,MDQSAR,MDQSAR19[1113]StrasbourgCros,1863[11]SARCrum2BrownFraserRichardsonRichetMeyerOvertonHammettTafeSARQSAR60HanschFujitaFreeWilson[1416],MDQSAR,MDQSAR,CADD,2112DQSAR21111Hansch2FujitaFree2WilsonHansch2Fujita[14,15,17],:lg1PC=algP+bEs++d,abd,,,,Hansch2Fujita(),,Hansch2FujitaFree2Wilson[15],:lg1PC=A0+ijPijAij,A0,Pijij(Pij=1)(Pij=0),Aijij,,,,,Hansch2FujitaFree2Wilson[15,16,18],,,[19]21112Randic[20]Kier[21],(0,1,2,3,),,X:lg1PC=b0+i(b2i-1iX+b2iiXV)(i=1,2)iXi,iXV,,[2224],,2DQSAR[2527],[1921,2730]21113(electrotopologicalstateindex,E2)E2KierHall[31],,,E2[32],,E2,E2,,1211[32]E2[23,26,27],,,Kier[33]E2211142DQSAR,(VMDE)(VADE),[3437],,(MEDV)[38](AEDV)[39],QSAR13C[3842]20,VSTVVHSEQSAR[43,44]2123DQSAR2DQSAR,3DQSAR,:,;,2D3D21211,3DQSAR,Cramer[45]1988(comparativemolecularfieldanalysis,CoMFA)CoMFA,,,,,,,CoMFA:(1),,;(2),Lennard2Jones6212Coulombic,CoMFA;(3)[46,47](partialleastsquare,PLS)(),3DQSAR;(4)CoMFA,,,,CoMFA:,;,;,,,CoMFA2DQSAR,CoMFA3D,,[4850]CoMFA,;[51],CoMFA,2,,CoMFA,CoMFAPLS(),,,,Gaillard[52,53]CoMFA;Kellogg[54]HINT(hydropathicinteraction)CoMFA,CoMFA3DQSAR,[5558]Kellogga[59]Poisson2BoltzmannZAPCoMFACoulombic,PLS22118,Schleifer[60]CoMFA,CoMSIAGRIDPGOLPE,DHP(blocking1,42dihydropyridines)QSAR,QSAR,CoMFA,KimuraHasegawa[61,62],CoMFA,127543,Tetko[63]CoMFA,:;PLS,CoMFACADDQSAR,2DQSAR,Hansch2FujitaQSAR[6466],,21212CoMFA3D:CoMSIA(comparativemolecularsimilarityindicesanalysis)1994Klebe[67][68]5:(),,,Viswanadhan[69],[70]CoMSIACoulombLennard2Jones6212,,cutoffCoMSIACoMFACoMFA[71],CoMSIA3DQSAR[68,72,73]CoMFA3DQSAR[7476](hypotheticalactivesitelattice,HASL),,CoMFACoMFA,,vanderWaalsHASLvanderWaals,(HASL),[75,76],artemisininQSAR,HASLCoMFA[77],HASLCoMFA21213Todeschini[78,79]3DQSARWHIM(weightedholisticinvariantmolecular),3:,;,,;,,WHIM,,,,WHIMWHIM,[79,80],,[81][82],WHIM[82][83],WHIM,,3D,3DQSAR,21214EVA(normalcoordinateeigenvalues)[84,85],:,,MOPAC;,,;,(L),,EVA3211(L),EVA[86],,EVA2[84][87],3DQSAR,Tuppurainen[88](EEVA)EVA,EVA,,3DQSAR,CADD,3DQSARQSAR3DQSAR,GRIDPGOLPE[89]DAPPER[90]LIV[91]MEP[92]CoMSA[93]2134DQSAR3DQSAR[94]3D,,3DQSAR1997,Hopfinger[95,96]4DQSAR,(ensembleprofile),4DQSAR,4D,(,),4DQSAR(gridcelloccupancydescriptors,GCODs),(interactionpharmacophoricelements,IPEs),,GCODGCOD[97]4DQSAR,IPEsBoltzmannaveragespatialPLS3DQSAR,4DQSAR3DQSAR:,,4DQSAR4DQSAR[95,96,98,99],Hopfinger[100]4DQSAR(virtualhighthroughputscreen),Santos2Filhoa[97]4DQSARHIV(42hydroxy25,62dihydropyroneanalogs)QSAR,,4DQSAR,,,HIVHopfinger4DQSAR,Vedani[101]4DQSAR,(quasi2atomisticreceptor,Quasar)4DQSAR,2[102],CoMFA2145DQSARX,,2002,VedaniDober[103,104]Quasar[102],5DQSAR4DQSAR3DQSAR,5DQSAR,,6:(steric)(electrostatic)(H2bond)(lipophilicitypotential)(energyminimization)(linearscheme),,5DQSAR5DQSAR,,,5DQSAR6,4DQSAR,5DQSAR,QSAR,[104]Vedani[104]5DQSAR22QSAR,5DQSAR42118018923,4DQSAR3DQSAR0175901641,5DQSAR4DQSAR3DQSAR5DQSAR,3DQSAR4DQSAR,,5DQSAR3,,2021,,,,21[105,106],,,,QSAR5DQSAR40,MDQSAR,,2,,,,,MDQSARCADD,MDQSAR,MDQSARUVIRMSNMR,,MDQSAR,MDQSAR,MDQSAR,,MDQSAR,[1]DrewsJ.Science,2000,287:19601963[2]DrewsJ.DrugDiscov.Today,2000,5:24[3]MllerG.Quant.Struct.Act.Relat.,2002,21:391396[4](ChenKX),(JiangHL),(JiRY).(Computer2AidedDrugDesign).:(Shanghai:ShanghaiScientificandTechnicalPublishers),2000.141195[5]MaduskuieTP,McNamaraKJ,RuY.J.Med.Chem.,1998,41:5362[6]VonItzsteinM,WuWY.Nature,1993,363:418423[7]XiongB,GuiCS,XuXY,etal.ActaPharmacol.Sin.,2003,24(6):497504[8]UrbinaJA,PayaresG,MolinaJ,etal.Science,1996,273:969971[9]SilvaCHTP,SanchesSM,TaftCA.JournalofMolecularGraphicsandModelling,2004,23:8997[10]KatritzkyAR,MaranU,LobanovVS,etal.J.Chem.Inf.Comput.Sci.,2000,40(1):118[11]KubinyiH.Quant.Struct.Act.Relat.,2002,21:348356[12]RekkerRF.Quant.Struct.Act.Relat.,1992,11:195199[13]VandeWaterbeemdH.Quant.Struct.Act.Relat.,1992,11:200204[14]Hansc