In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors

International Journal of Molecular Sciences

Ming Hao⁴  Xiaole Zhang⁵  Hong Ren¹  Yan Li⁴  Shuwei Zhang⁴  Fang Luo²  Mingjuan Ji²  Guohui Li³ 

[1] Department of Ophthalmology, Qi Lu Hospital, Medical School of Shandong University, Jinan, 250012, China; E-Mail:;College of Chemistry and Chemical Engineering, Graduate School of the Chinese Academy of Sciences, Beijing, 100049, China; E-Mails:;Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China; E-Mail:;Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116023, China; E-Mails:;Department of Mathematical Sciences, Dalian University of Technology, Dalian, Liaoning, 116023, China; E-Mail:

关键词: 3D-QSAR;    molecular dynamics;    FBPase inhibitors;    CoMFA;    CoMSIA;   

DOI  :  10.3390/ijms12118161

来源: mdpi

【 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_ncv², q² values of 0.986, 0.514 for internal validation, and r_pred², r_m² 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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.