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題 名 | Computational Screening and QSAR Analysis for Design of AMP-Activated Protein Kinase Agonist |
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作 者 | Huang, Hung-jin; Chen, Chien-yu; Chen, Hsin-yi; Tsai, Fuu-jen; Chen, Calvin Yu-chian; | 書刊名 | Journal of the Taiwan Institute of Chemical Engineers |
卷 期 | 41:3 2010.05[民99.05] |
頁 次 | 頁352-359 |
分類號 | 460.02 |
關鍵詞 | AMP-activated protein kinase; Docking; Molecular simulation; QSAR; |
語 文 | 英文(English) |
英文摘要 | Abstract AMP-activated protein kinase (AMPK) senses the cellular energy state by monitoring the AMP in various eukaryotes. The activated AMPK regulates a wide range of important pathways which cause diabetes, obesity, metabolic aberrant, and also breast cancer. In this study, the crystal structure of yeast AMPK was used as a template to construct the reliable homology model of human AMPK with corresponding binding site. The quantitative structure–activity relationship (QSAR) models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models, were utilized to obtain the pharmacophore feature. By virtual screening the data, the top eight phenylamide compounds screened by “De novo evolution” were selected to design new ligands for AMPK. A total of 531 derivatives were generated subsequently. All the potent ligands, same as AMP and AICAR, carried H-bond interacting with the key interactive amino acids of AMPK. The features of the derivatives were also fitted with the CoMFA and CoMSIA models. Thus, these data suggested that the phenylamide derivates might be the potent AMPK agonists. |
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