Abstract
IMP metallo-β-lactamases (MBLs) confer broad-spectrum resistance to β-lactam antibiotics such as imipenem and escape the action of almost all clinically used β-lactamase inhibitors. We conducted three-dimensional quantitative structure–activity relationships (3D-QSAR) for a series of IMP-1 MBL inhibitors with the aid of docking-based alignment. While the 3D-QSAR models were created based on a training set of 41 compounds, their external predictivity was validated using a test set of eight compounds. The study has resulted in two types of satisfactory 3D-QSAR models for predicting the biological activity of new compounds: CoMFA model (r 2 = 0.989; \( r_{\text{pre}}^{ 2} = 0. 8 4 3 \)) and CoMSIA model (r 2 = 0.968; \( r_{\text{pre}}^{ 2} = 0. 9 5 7 \)). Our work will facilitate the design and optimization of new potential inhibitors.
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Acknowledgments
This study was supported by the China National Nature Science Foundation (Grant No. 30973667), Hi-Tech Research and Development Program of China-863 Program (No. 2007AA02Z101) and the Fundamental Research Funds for the Central Universities of China (No. JKZ2009007). The authors thank Haoliang Yuan (Department of Basic Sciences, China Pharmaceutical University) for his help on software usage.
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Chen, J., Yu, R., Shen, B. et al. Docking-based 3D-QSAR modeling of the inhibitors of IMP metallo-β-lactamase. Med Chem Res 22, 1730–1739 (2013). https://doi.org/10.1007/s00044-012-0172-1
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DOI: https://doi.org/10.1007/s00044-012-0172-1