[1]常美佳,罗盛,杨旭曙,等.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[J].南京师范大学学报(自然科学版),2015,38(03):31.
ChangMeijia,LuoSheng,YangXushu,et al.3D-QSARStudiesof2,4-ThiazolidinedionesasAldoseReductaseInhibitorsUsingCoMFA,CoMSIAandMolecularDocking[J].Journal of Nanjing Normal University(Natural Science Edition),2015,38(03):31.
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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(
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《南京师范大学学报》(自然科学版)[ISSN:1001-4616/CN:32-1239/N]
- 卷:
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第38卷
- 期数:
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2015年03期
- 页码:
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31
- 栏目:
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化学
- 出版日期:
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2015-09-30
文章信息/Info
- Title:
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3D-QSARStudiesof2,4-ThiazolidinedionesasAldoseReductaseInhibitorsUsingCoMFA,CoMSIAandMolecularDocking
- 作者:
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常美佳1; 罗盛1; 杨旭曙1; 张一鸣2; 孙成3; 王连生3
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(1.南京医科大学药学院,江苏南京211166)
(2.南京医科大学基础医学院,江苏南京210029)
(3.南京大学环境学院,江苏南京210093)
- Author(s):
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ChangMeijia1; LuoSheng1; YangXushu1; ZhangYiming2; SunCheng3; WangLiansheng3
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(1.SchoolofPharmacy,NanjingMedicalUniversity,Nanjing211166,China)
(2.SchoolofBasicMedicalSciences,NanjingMedicalUniversity,Nanjing210029,China)
(3.StateKeyLaboratoryofPollutionControlandResourcesReuse,SchoolofEnvironment,NanjingUniversity,Nanjing210046,China)
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- 关键词:
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噻唑烷二酮; 醛糖还原酶抑制剂; 3D-QSAR; 分子对接
- Keywords:
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2; 4-Thiazolidinediones; Aldosereductaseinhibitors; 3D-QSAR; moleculardocking
- 分类号:
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O641.3
- 文献标志码:
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A
- 摘要:
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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.
- Abstract:
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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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备注/Memo
- 备注/Memo:
-
收稿日期:2013-06-08.
基金项目:国家自然科学基金面上项目(21277074)、国家自然科学基金青年科学基金项目(81302458)、江苏省高校自然科学基金项目(11KJB180006)、南京医科大学自然科学基金重点项目(09NJMUZ16).
通讯联系人:杨旭曙,博士,副教授,研究方向:环境毒理学.E-mail:yangxushu@njmu.edu.cn
更新日期/Last Update:
2015-09-30