Abstract
V600EBRAF have been identified as new promising targets for the design of novel anticancer agents. It is reported that the inhibitors based on 2,3-dihydroimidazo[4,5]pyridin-2-one scaffold and a meta-substituted middle ring exhibit potent inhibitory activities toward V600EBRAF. To investigate how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative structure–activity relationship (3D-QSAR) methods were performed. The bioactive conformation was explored by docking one potent compound 1 into the active site of BRAF in its DFG-out inactive conformation. The constructed CoMFA and CoMSIA models produced statistically significant results with the cross-validated correlation coefficients q 2 of 0.563 and 0.624, non-cross-validated correlation coefficients r 2 of 0.982 and 0.962, and predicted correction coefficients r 2pred of 0.822 and 0.875, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design of a series of new inhibitors of this class with predicted excellent activities. Thus, these models may be used as an efficient tool to predict the inhibitory activities and to guide the future rational design of 2,3-dihydroimidazo[4,5]pyridin-2-one derivatives with a meta substitution pattern as BRAF inhibitors with potent activities.
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Acknowledgments
The authors gratefully acknowledge financial support from National Science Foundation of China (No. 81202413), National Science Foundation of China (No. 81173097), International Science and Technology Cooperation Base of Guangdong Provincial Department of Science and Technology (No. 2009B050900006), Science and Technology Planning Project of Guangdong Province (No. 2011B050200006), and Science and Technology Bureau of Guangzhou (No. 2010V1-E00531-3).
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Wu, X., Wan, S., Li, Z. et al. 3D-QSAR study on 2,3-dihydroimidazo[4,5]-pyridin-2-one derivatives with a meta substitution pattern as V600EBRAF inhibitors. Med Chem Res 23, 587–602 (2014). https://doi.org/10.1007/s00044-013-0633-1
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DOI: https://doi.org/10.1007/s00044-013-0633-1