Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening
MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E at Ser209 to control the translation of certain mRNAs and regulate the process of cell proliferation, cell migration and invasion, etc. Development of MNK inhibitors would be an effective treatment for related di...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/20/7/429 |
| _version_ | 1827618892596379648 |
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| author | Xin Jin Maowei Li Tingting Qiu Rilei Yu Tao Jiang |
| author_facet | Xin Jin Maowei Li Tingting Qiu Rilei Yu Tao Jiang |
| author_sort | Xin Jin |
| collection | DOAJ |
| description | MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E at Ser209 to control the translation of certain mRNAs and regulate the process of cell proliferation, cell migration and invasion, etc. Development of MNK inhibitors would be an effective treatment for related diseases. We used the MarineChem3D database to identify hit compounds targeting the protein MNK1 and MNK2 through high-throughput screening. Compounds from the phorbazole family showed good interactions with MNK1, and phorbazole C was selected as our hit compound. By analyzing the binding mode, we designed and synthesized 29 derivatives and evaluated their activity against MNKs, of which, six compounds showed good inhibition to MNKs. We also confirmed three interactions between this kind of compound and MNK1, which are vital for the activity. In conclusion, we report series of novel MNK inhibitors inspired from marine natural products and their relative structure–activity relationship. This will provide important information for further developing MNK inhibitors based on this kind of structure. |
| first_indexed | 2024-03-09T10:15:45Z |
| format | Article |
| id | doaj.art-c5bd1d770ee9459bad265a7fc332c304 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-09T10:15:45Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-c5bd1d770ee9459bad265a7fc332c3042023-12-01T22:23:42ZengMDPI AGMarine Drugs1660-33972022-06-0120742910.3390/md20070429Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput ScreeningXin Jin0Maowei Li1Tingting Qiu2Rilei Yu3Tao Jiang4School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaMNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E at Ser209 to control the translation of certain mRNAs and regulate the process of cell proliferation, cell migration and invasion, etc. Development of MNK inhibitors would be an effective treatment for related diseases. We used the MarineChem3D database to identify hit compounds targeting the protein MNK1 and MNK2 through high-throughput screening. Compounds from the phorbazole family showed good interactions with MNK1, and phorbazole C was selected as our hit compound. By analyzing the binding mode, we designed and synthesized 29 derivatives and evaluated their activity against MNKs, of which, six compounds showed good inhibition to MNKs. We also confirmed three interactions between this kind of compound and MNK1, which are vital for the activity. In conclusion, we report series of novel MNK inhibitors inspired from marine natural products and their relative structure–activity relationship. This will provide important information for further developing MNK inhibitors based on this kind of structure.https://www.mdpi.com/1660-3397/20/7/429MNKeIF4Ephorbazole Chigh-throughput screeningstructure-activity relationship |
| spellingShingle | Xin Jin Maowei Li Tingting Qiu Rilei Yu Tao Jiang Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening Marine Drugs MNK eIF4E phorbazole C high-throughput screening structure-activity relationship |
| title | Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
| title_full | Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
| title_fullStr | Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
| title_full_unstemmed | Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
| title_short | Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening |
| title_sort | design synthesis and evaluation of novel phorbazole c derivatives as mnk inhibitors through virtual high throughput screening |
| topic | MNK eIF4E phorbazole C high-throughput screening structure-activity relationship |
| url | https://www.mdpi.com/1660-3397/20/7/429 |
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