Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation
Macrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis. Herein, a series of compounds (termed as Hits 1–6) were discovered based on pha...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2501378 |
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| author | Shang Zhu Shudan Yang Yao Chen Miao-Miao Niu Jun Wang Jindong Li Xuehua Pu |
| author_facet | Shang Zhu Shudan Yang Yao Chen Miao-Miao Niu Jun Wang Jindong Li Xuehua Pu |
| author_sort | Shang Zhu |
| collection | DOAJ |
| description | Macrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis. Herein, a series of compounds (termed as Hits 1–6) were discovered based on pharmacophore modelling, molecular docking, and interaction analysis. The biaryltriazole inhibitor 3a was used as the positive control. MST and ITC experiments showed that compared to 3a, Hit-1 possessed the highest affinity with MIF. MD simulations exhibited that Hit-1 stably bound to the active pocket of MIF. Pull down experiment showed that Hit-1 could interfere with the binding of MIF to CD74. Furthermore, RT-qPCR demonstrated that Hit-1 suppressed the release of pro-inflammatory cytokines in macrophages including TNF-α, IL-6, and IL-1β. These data demonstrate that Hit-1 may be a promising and high-affinity candidate compound treating sepsis. |
| format | Article |
| id | doaj-art-714b5d19d1314c1c9a56a7dfd86eb9d3 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-714b5d19d1314c1c9a56a7dfd86eb9d32025-08-20T02:06:57ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2501378Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluationShang Zhu0Shudan Yang1Yao Chen2Miao-Miao Niu3Jun Wang4Jindong Li5Xuehua Pu6Department of Critical Care Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Infection Control and Emergency Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Infection Control and Emergency Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, ChinaInstitute of Clinical Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, ChinaDepartment of Critical Care Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, ChinaMacrophage migration inhibitory factor (MIF) plays a crucial role in disrupting immune homeostasis and was overexpressed in immune cells. The inhibitors of MIF inhibit the release of inflammatory factors to treat sepsis. Herein, a series of compounds (termed as Hits 1–6) were discovered based on pharmacophore modelling, molecular docking, and interaction analysis. The biaryltriazole inhibitor 3a was used as the positive control. MST and ITC experiments showed that compared to 3a, Hit-1 possessed the highest affinity with MIF. MD simulations exhibited that Hit-1 stably bound to the active pocket of MIF. Pull down experiment showed that Hit-1 could interfere with the binding of MIF to CD74. Furthermore, RT-qPCR demonstrated that Hit-1 suppressed the release of pro-inflammatory cytokines in macrophages including TNF-α, IL-6, and IL-1β. These data demonstrate that Hit-1 may be a promising and high-affinity candidate compound treating sepsis.https://www.tandfonline.com/doi/10.1080/14756366.2025.2501378MIFstructure-based pharmacophore modellingmolecular dockingMD simulationsbiological evaluation |
| spellingShingle | Shang Zhu Shudan Yang Yao Chen Miao-Miao Niu Jun Wang Jindong Li Xuehua Pu Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation Journal of Enzyme Inhibition and Medicinal Chemistry MIF structure-based pharmacophore modelling molecular docking MD simulations biological evaluation |
| title | Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation |
| title_full | Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation |
| title_fullStr | Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation |
| title_full_unstemmed | Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation |
| title_short | Identification of a novel and high affinity MIF inhibitor via structure-based pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation |
| title_sort | identification of a novel and high affinity mif inhibitor via structure based pharmacophore modelling molecular docking molecular dynamics simulations and biological evaluation |
| topic | MIF structure-based pharmacophore modelling molecular docking MD simulations biological evaluation |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2501378 |
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