| 摘要: |
| 细胞外信号调节激酶2(ERK2)是恶性肿瘤发生发展过程中的关键激酶，目前还没有靶向ERK2的药物获批上市。本研究旨在获得结构新颖的靶向ERK2小分子抑制剂。通过质粒构建、蛋白表达与体外激酶活性测试，针对实验室构建的北部湾次级代谢产物及化学合成化合物库开展生物活性筛选，利用分子对接分别阐明化合物与ERK2激酶的结合模式及作用机理。最终获得6-甲氧基红镰霉素B、异红镰霉素及嘧啶脲类的5个具有较高抑制剂活性的苗头化合物，其最佳IC50分别为4.17±1.82、13.39±0.93、27.85±2.55、19.14±1.02和8.55±3.72 μmol/L，分别展开其与ERK2激酶的结合模式及作用机理的讨论。本研究明确了5个化合物对ERK2激酶具有抑制活性，初步探讨了它们与ERK2激酶的作用机理，为进一步靶向ERK2的药物设计提供了参考。 |
| 关键词: 细胞外信号调节激酶2（ERK2） 分子对接 蛋白表达 活性筛选 结合模式 |
| DOI： |
| 投稿时间：2024-01-09修订日期：2024-02-14 |
| 基金项目: |
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| Bioassay screening and binding mode study of inhibitors targeting at ERK2 |
|
Wu xiru, Wang Lingzhi, Gao Yalei, Yang Min, Liu Yonghong, Xu Xinya, Liu Kai
|
| (Institute of Marine Drugs) |
| Abstract: |
| Extracellular signaling regulatory kinase 2 (ERK2) is a key kinase involved in the development and progression of malignant tumors. Currently, there is not FDA approved drugs specially targeting at ERK2 kinase. In order to explore structurally novel inhibitors targeting at ERK2 kinase, we constructed hERK2 plasmid for protein expression and kinase activity assays in vivo. we conducted bioassay screening on in-house molecular library, which consists of natural product isolated from Beibu gulf and chemically synthesized compounds of interest. Molecular docking was also employed to elucidate the binding modes and mechanisms of these compounds with the ERK2 kinase. Five hit compounds, 6-methoxy-rubrofusarin B, isorubrofusarin and 2-pyridyl urea with IC50 of 4.17±1.82, 13.39±0.93, 27.85±2.55, 19.14±1.02 and 8.55±3.72 μmol/L were identified, respectively. Their putative binding modes were disclosed by molecular docking. In summary, five inhibitors were refined out by bioassay and their binding modes were illustrated in this study. These results would be benefit to the drug discovery of targeting at ERK2 kinase. |
| Key words: Extracellular regulated protein kinase2 (ERK2) Molecular Docking Protein Expression Bioassay Screening Binding Mode |
