Discovery of novel cGAS inhibitors based on natural flavonoids
文献类型：期刊论文
| 作者 | Li, Jiameng4,5; Xiong, Muya3,4; Liu, Jiayuan4; Zhang, Fengping2,4; Li, Minjun1; Zhao, Wenfeng4; Xu, Yechun2,3,4,5
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| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2023-11-01 |
| 卷号 | 140页码:14 |
| ISSN号 | 0045-2068 |
| 关键词 | Cyclic GMP-AMP synthase Inhibitor Flavonoids Crystal structure Virtual screening |
| DOI | 10.1016/j.bioorg.2023.106802 |
| 通讯作者 | Zhao, Wenfeng(zhaowenfeng@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn) |
| 英文摘要 | Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases. Flavonoids, a typical class of natural products, are known for their anti-inflammatory activities. Although cGAS is closely associated with inflammation, the potential effects of natural flavonoid compounds on cGAS have been rarely studied. Therefore, we screened an in-house natural flavonoid library by pyrophosphatase (PPiase) coupling assay and identified novel cGAS inhibitors baicalein and baicalin. Subsequently, crystal structures of the two natural flavonoids in complex with human cGAS were determined, which provide mech-anistic insight into the anti-inflammatory activities of baicalein and baicalin at the molecular level. After that, a virtual screening based on the crystal structures of baicalein and baicalin in complex with human cGAS was performed. As a result, compound C20 was identified to inhibit both human and mouse cGAS with IC50 values of 2.28 and 1.44 & mu;M, respectively, and its detailed interactions with human cGAS were further revealed by the X-ray crystal structure determination. These results demonstrate the potential of natural products used as hits in drug discovery and provide valuable hints for further development of cGAS inhibitors. |
| WOS关键词 | CYCLIC GMP-AMP ; DNA SENSOR ; SYNTHASE ; MODEL ; INFLAMMATION ; PROTEIN ; BAICALEIN ; DOCKING ; PHASE ; GLIDE |
| 资助项目 | National Natural Science Foundation of China[22277130] ; Science and Technology Commission of Shanghai Municipality[20430780300] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| WOS记录号 | WOS:001074043200001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307164]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Wenfeng; Xu, Yechun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai Adv Res Inst, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Jiameng,Xiong, Muya,Liu, Jiayuan,et al. Discovery of novel cGAS inhibitors based on natural flavonoids[J]. BIOORGANIC CHEMISTRY,2023,140:14. |
| APA | Li, Jiameng.,Xiong, Muya.,Liu, Jiayuan.,Zhang, Fengping.,Li, Minjun.,...&Xu, Yechun.(2023).Discovery of novel cGAS inhibitors based on natural flavonoids.BIOORGANIC CHEMISTRY,140,14. |
| MLA | Li, Jiameng,et al."Discovery of novel cGAS inhibitors based on natural flavonoids".BIOORGANIC CHEMISTRY 140(2023):14. |
入库方式： OAI收割
来源：上海药物研究所
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