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In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors
Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116023, China
Department of Mathematical Sciences, Dalian University of Technology, Dalian, Liaoning, 116023, China
Department of Ophthalmology, Qi Lu Hospital, Medical School of Shandong University, Jinan, 250012, China
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
College of Chemistry and Chemical Engineering, Graduate School of the Chinese Academy of Sciences, Beijing, 100049, China
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian, Liaoning, 116023, China
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 8 October 2011; in revised form: 10 November 2011 / Accepted: 16 November 2011 / Published: 18 November 2011
Abstract: 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 rncv2, q2 values of 0.986, 0.514 for internal validation, and rpred2, rm2 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.
Keywords: 3D-QSAR; molecular dynamics; FBPase inhibitors; CoMFA; CoMSIA
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Hao, M.; Zhang, X.; Ren, H.; Li, Y.; Zhang, S.; Luo, F.; Ji, M.; Li, G.; Yang, L. In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors. Int. J. Mol. Sci. 2011, 12, 8161-8180.
Hao M, Zhang X, Ren H, Li Y, Zhang S, Luo F, Ji M, Li G, Yang L. In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors. International Journal of Molecular Sciences. 2011; 12(11):8161-8180.
Hao, Ming; Zhang, Xiaole; Ren, Hong; Li, Yan; Zhang, Shuwei; Luo, Fang; Ji, Mingjuan; Li, Guohui; Yang, Ling. 2011. "In Silico Identification of Structure Requirement for Novel Thiazole and Oxazole Derivatives as Potent Fructose 1,6-Bisphosphatase Inhibitors." Int. J. Mol. Sci. 12, no. 11: 8161-8180.