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2，4-噻唑烷二酮类醛糖还原酶抑制剂的三维定量结构-活性关系及分子对接研究

Keywords: 噻唑烷二酮, 醛糖还原酶抑制剂, 3D-QSAR, 分子对接
2, 4-Thiazolidinediones, Aldosereductaseinhibitors, 3D-QSAR, moleculardocking

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Abstract:

醛糖还原酶抑制剂通过抑制多元醇通路中醛糖的还原而有希望成为治疗慢性糖尿病的新药，这促进了新型醛糖还原酶（ALR2）抑制剂的研制.本文采用两种3D-QSAR方法，即比较分子力场分析（CoMFA）和比较相似性指数分析（CoMSIA）方法，研究2，4-噻唑烷二酮类醛糖还原酶抑制剂结构与活性之间的关系.采用原子契合（相同骨架结构）、场契合和基于分子对接3种分子叠合方式构建CoMFA和CoMSIA模型.基于原子契合方式构建的模型为最佳预测模型（CoMFAr2=0.922，q2LOO=0.707；CoMSIAr2=0.917，q2LOO=0.762）.此模型进一步通过12个化合物组成的样本外测试集进行验证，结果由CoMFA和CoMSIA模型得到的测试集外部验证系数（r2pred）分别为0.824和0.883.CoMFA和CoMSIA的力场系数等高图的分析结果与分子对接的结果一致.CoMFA和CoMSIA方法结合分子对接研究有助于揭示抑制剂与醛糖还原酶之间的相互作用以及影响醛糖还原酶抑制剂活性的化合物的结构特征，这些为新型醛糖还原酶抑制剂的理性设计提供了有益的信息.
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

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