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个人信息Personal Information
教授
硕士生导师
性别:男
毕业院校:大连理工大学
学位:硕士
所在单位:化工学院
电子邮箱:zswei@dlut.edu.cn
In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors
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论文类型:期刊论文
发表时间:2011-11-01
发表刊物:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
收录刊物:Scopus、SCIE、PubMed
卷号:12
期号:11
页面范围:8161-8180
ISSN号:1422-0067
关键字:3D-QSAR; molecular dynamics; FBPase inhibitors; CoMFA; CoMSIA
摘要:Fructose 1,6-bisphosphatase (FBPase) has been identified as a drug discovery target for lowering glucose in type 2 diabetes mellitus. In this study, a large series of 105 FBPase inhibitors were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in potency. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(ncv)(2), q(2) values of 0.986, 0.514 for internal validation, and r(pred)(2), r(m)(2) statistics of 0.902, 0.828 statistics for external validation. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules. (1) Substituents with a proper length and size at the C5 position of the thiazole core are required to enhance the potency; (2) A small and electron-withdrawing group at the C2 position linked to the thiazole core is likely to help increase the FBPase inhibition; (3) Substituent groups as hydrogen bond acceptors at the C2 position of the furan ring are favored. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential FBPase inhibitors.