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《南京师大学报（自然科学版）》[ISSN:1001-4616/CN:32-1239/N]

Issue:

2015年03期

Page:

31-

Research Field:

化学

Publishing date:

Info

Title:

3D-QSARStudiesof2，4-ThiazolidinedionesasAldoseReductaseInhibitorsUsingCoMFA，CoMSIAandMolecularDocking

Author(s):

ChangMeijia¹; LuoSheng¹; YangXushu¹; ZhangYiming²; SunCheng³; WangLiansheng³

（1.SchoolofPharmacy，NanjingMedicalUniversity，Nanjing211166，China)
（2.SchoolofBasicMedicalSciences，NanjingMedicalUniversity，Nanjing210029，China)
（3.StateKeyLaboratoryofPollutionControlandResourcesReuse，SchoolofEnvironment，NanjingUniversity，Nanjing210046，China)

Keywords:

2; 4-Thiazolidinediones; Aldosereductaseinhibitors; 3D-QSAR; moleculardocking

PACS:

O641.3

DOI:

-

Abstract:

Aldosereductase(ALR2)inhibitorsarepromisingagentsforchronicdiabeticcomplicationtherapybypreventingthereductionofglucoseinthepolyolpathway，whichpromotestodevelopnovelALR2inhibitors.Twokindsoftechniques，comparativemolecularfieldanalysis(CoMFA)andcomparativemolecularsimilarityindicesanalysis(CoMSIA)，wereemployedforstudyingaseriesof5-arylidene-2，4-thiazolidinedionesasaldosereductaseinhibitors.Withthestrategiesofcommonsubstructure-basedalignmentandfield-fitalignment，thelowestenergyconformationswereusedtodeveloptheligand-basedmodelsofthree-dimensionalquantitativestructure-activityrelationship(3D-QSAR).Thebioactiveconformationobtainedbydockingall5-arylidene-2，4-thiazolidinedionesderivativesintotheactivesiteofaldosereductase(PBDID：1ah3)wasappliedforthedevelopmentofreceptor-basedmodel.Statisticallysignificantmodelofligand-based3D-QSARfromthecommonsubstructure-basedalignmentexhibitedthebestpredictivepower(CoMFAr²=0.922，q²=0.707；CoMSIAr²=0.917，q²=0.762).Themodelwasfurtherconfirmedbyanalyzing12setsofcompoundswithdiversestructure.Theresultsshowedhighpredictiver²valuesof0.824forCoMFAand0.883forCoMSIArespectively.ThemoleculardockinganalysisrevealedthatbothCoMFAandCoMSIAcontourmapsforsteric，electrostatic，hydrophobic，andhydrogen-bondinginteractionsmatchedwell.ThecombinationofCoMFAandCoMSIAwithmoleculardockingishelpfultounderstandtheinteractionandthestructure-activityrelationshipbetweenALR2anditsinhibitor.ThepresentresultsprovideavaluableguidanceforrationallydesigningARL2inhibitors.

References:

［1］PfeiferMA，SchumerMP.Clinicaltrialsofdiabeticneuropathy：past，present，andfuture［J］.Diabetes，1995，44：1?355-1361.
［2］WilliamsonJR，OstrowE，EadesD，etal.Glucose-inducedmicrovascularfunctionalchangesinnondiabeticratsarestereospecificandarepreventedbyanaldosereductaseinhibitor［J］.JClinInvest，1990，85：1167-1172.
［3］BrownleeM.Biochemistryandmolecularcellbiologyofdiabeticcomplications［J］.Nature，2001，414：813-820.
［4］OyamaT，MiyasitaY，WatanabeH，etal.Theroleofpolyolpathwayinhighglucose-inducedendothelialcelldamages［J］.DiabetesResClinPract，2006，73：227-234.
［5］CostanitinoL，RastelliG，VianelloP，etal.Diabetescomplicationsandtheirpotentialprevention：aldosereductaseinhibitionandotherapproaches.DiabetesComplicationsandPotentialPrevention［J］.MedResRev，1999，19：3-22.
［6］KadorPF.Theroleofaldosereductaseinthedevelopmentofdiabeticcomplications［J］.MedResRev，1988，8：325-352.
［7］KadorPF，KinoshitaJH，SharplessNJ.Aldosereductaseinhibitors：apotentialnewclassofagentsforthepharmacologicalcontrolofcertaindiabeticcomplications［J］.JMedChem，1985，28：841-849.
［8］SargesR，OatesPJ.Aldosereductaseinhibitors：recentdevelopments［J］.ProgDrugRes，1993，40：99-161.
［9］CostantinoL，RastelliG，CignarellaG，etal.Newaldosereductaseinhibitorsaspotentialagentsforthepreventionoflong-termdiabeticcomplications［J］.ExpOpinTherPatents，1997，7：843-858.
［10］LarsonER，LipinskiCA，SargesR.Medicinalchemistryofaldosereductaseinhibitors［J］.MedResRev，1988，8：159-186.
［11］CostantinoL，RastelliG，GamberoniMC，etal.Pharmacologicalapproachestothetreatmentofdiabeticcomplications［J］.ExpOpinTherPatents，2000，10：1245-1262.
［12］FresneauP，CussacM，MorandJ，etal.Synthesis，activity，andmolecularmodelingofnew2，4-dioxo-5-（naphthylmethylene）-3-thiazolidineaceticacidsand2-thioxoanaloguesaspotentaldosereductaseinhibitors［J］.JMedChem，1998，41：4706-4715.
［13］SohdaT，MizunoK，ImamiyaE，etal.Studiesonantidiabeticagents.II.Synthesisof5-［4.（1-methylcyclohexyl-methoxy）benzyl］thiazolidine-2，4-dione（ADD-3878）anditsderivatives［J］.ChemPharmBull，1982，30：3580-3600.
［14］ZaskA，JirkovskyI，NowickiJW，etal.Synthesisandantihyperglycemicactivityofnovel5-（naphthalenylsulfonyl）-2，4-thiazolidinediones［J］.JMedChem，1990，33：1418-1423.
［15］MomoseY，MeguroK，IkedaH，etal.Studiesonantidiabeticagents.X.Synthesisandbiologicalactivitiesofpioglitazoneandrelatedcompounds［J］］.ChemPharmBull，1991，39：1440-1445.
［16］BrunoG，CostantinoL，CuringaC，etal.Synthesisandaldosereductaseinhibitoryactivityof5-arylidene-2，4-thiazolidinedionesy［J］.BioorgMedChem，2002，10：1077-1084.
［17］MaccariR，OttanaR，CuringaC，etal.Structure-activityrelationshipsandmolecularmodellingof5-arylidene-2，4-thiazolidinedionesactiveasaldosereductaseinhibitors［J］.BioorgMedChem，2005，13：2809-2823.
［18］MaccariR，OttanaR，CiurleoR，etal.Evaluationofinvitroaldoseredutaseinhibitoryactivityof5-arylidene-2，4-thiazolidinediones［J］.BioorgMedChemLett，2007，17：3886-3893.
［19］SambasivaraoSV，SoniLK，GuptaAK，etal.Quantitativestructure-activityanalysisof5-arylidene-2，4-thiazolidinedionesasaldosereductaseinhibitors［J］.BioorgMedChemLett，2006，16：512-520.
［20］CramerIIIRD，PattersonDE，BunceJD.Comparativemolecularfieldanalysis（CoMFA）.1.Effectofshapeonbindingofsteroidstocarrierproteins［J］.JAmChemSoc，1988，110：5959-5967.
［21］KlebeG，AbrahamU，MietznerT.Molecularsimilarityindicesinacomparativeanalysis（CoMSIA）ofdrugmoleculestocorrelateandpredicttheirbiologicalactivity［J］.JMedChem，1994，37：4130-4146.
［22］TriposAssociates.SybylVersion7.3［M］.St.Louis：TriposAssociates，2006.
［23］ClarkM，CramerIIIRD，OpdenboschNV.Validationofthegeneral-purposeTRIPOS5.2forcefield［J］.JComputChem，1989，10：982-1012.
［24］GasteigerJ，MarsilliM.Iterativepartialequalizationoforbitalelectronegativity—arapidaccesstoatomiccharges［J］.Tetrahedron，1980，36：3219-3228.
［25］JainAN.Surflex：fullyautomaticflexiblemoleculardockingusingamolecularsimilarity-basedsearchengine［J］.JMedChem，2003，46：499-511.
［26］WeinerSJ，KollmanPA，CaseDA，etal.Anewforcefieldformolecularmechanicalsimulationofnucleicacidsandproteins［J］.JAmChemSoc，1984，106：765-784.
［27］WoldS，RuheA，WoldH，etal.Thecovarianceprobleminlinearregression.Thepartialleastsquares（PLS）approachtogeneralizedinverses［J］.SIAMJSciStatComput，1984，5：735-743.
［28］WoldS.Crossvalidatoryestimationofthenumberofcomponentsinfactorandprincipalcomponentsmodels［J］.Technometrics，1978，4：397-405.

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Last Update: 2015-09-30