Design,Synthesis, Biological Evaluation,and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors |
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| Authors: | Xiangcong Wang Moxuan Zhang Ranran Zhu Zhongshan Wu Fanhong Wu Zhonghua Wang Yanyan Yu |
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| Affiliation: | 1.School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201400, China; (X.W.); (M.Z.); (R.Z.); (Z.W.); (F.W.);2.Shanghai Engineering Research Center of Green Fluoropharmaceutical Technology, 100 Haiquan Road, Shanghai 201400, China |
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| Abstract: | PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87). |
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| Keywords: | PI3Kα inhibitor, 3D-QSAR, molecular docking, molecular dynamics simulation, benzimidazoles, anticancer |
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