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Molecular modeling studies on phosphonic acid-containing thiazole derivatives: design for fructose-1,6-bisphosphatase inhibitors

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Abstract

Presently, an in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase (FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The CoMFA and CoMSIA models using 51 molecules in the training set gave r 2cv values of 0.675 and 0.619, r 2 values of 0.985 and 0.979, respectively. The systemic external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r 20 values of 0.995 and 0.994, r 2m(test) values of 0.887 and 0.860, respectively. The 3D contour maps of the CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship for the inhibitors. Molecular docking studies revealed that a phosphonic group was essential for binding to the AMP binding site, and some key features were also identified. The analyses of the 3D contour plots and molecular docking results permitted interesting conclusions about the effects of different substituent groups at different positions of the common scaffold, which might guide the design of novel FBPase inhibitors with higher activity and bioavailability. A set of 60 new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.

An in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase (FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response

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Acknowledgments

We gratefully acknowledge support for this research from the National Natural Science Foundation of China (Grant No. 81072554).

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Authors and Affiliations

  1. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China

    Ping Lan, Zhi-Wei Wu, Wan-Na Chen, Ping-Hua Sun & Wei-Min Chen

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  1. Ping Lan
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  2. Zhi-Wei Wu
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Correspondence to Wei-Min Chen.

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Lan, P., Wu, ZW., Chen, WN. et al. Molecular modeling studies on phosphonic acid-containing thiazole derivatives: design for fructose-1,6-bisphosphatase inhibitors. J Mol Model 18, 973–990 (2012). https://doi.org/10.1007/s00894-011-1134-0

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  • DOI: https://doi.org/10.1007/s00894-011-1134-0

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