Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors
文献类型：期刊论文
| 作者 | Liu, Sijiu3; Zeng, Li-Fan2; Wu, Li3; Yu, Xiao; Xue, Ting2; Gunawan, Andrea M.1; Long, Ya-Qiu2; Zhang, Zhong-Yin1,3 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2008-12-17 |
| 卷号 | 130期号:50页码:17075-17084 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/ja8068177 |
| 文献子类 | Article |
| 英文摘要 | There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties. |
| WOS关键词 | PROTEIN-TYROSINE-PHOSPHATASE ; HIGHLY EFFICIENT PREPARATION ; HUMAN BREAST-CANCER ; HIV-1 INTEGRASE ; INSULIN SENSITIVITY ; CRYSTAL-STRUCTURE ; LIGAND-BINDING ; LOOP DYNAMICS ; ACTIVE-SITE ; 1B |
| 资助项目 | National Institutes of Health[CA 126937] ; National Natural Science Foundation of China[30721005] ; National Natural Science Foundation of China[20872154] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000263320400048 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279406]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, Ya-Qiu |
| 作者单位 | 1.Indiana Univ, Sch Med, Chem Genom Core Facil, Indianapolis, IN 46202 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA; |
| 推荐引用方式 GB/T 7714 | Liu, Sijiu,Zeng, Li-Fan,Wu, Li,et al. Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2008,130(50):17075-17084. |
| APA | Liu, Sijiu.,Zeng, Li-Fan.,Wu, Li.,Yu, Xiao.,Xue, Ting.,...&Zhang, Zhong-Yin.(2008).Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,130(50),17075-17084. |
| MLA | Liu, Sijiu,et al."Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 130.50(2008):17075-17084. |
入库方式： OAI收割
来源：上海药物研究所
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