Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening
USP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted...
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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/10.1080/14756366.2025.2518191 |
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| author | Hobin Lee Sunghoon Hurh Soomin Kang Jihwan Yoon Jong-Ik Hwang Derek T. Logan Hong-Rae Kim |
| author_facet | Hobin Lee Sunghoon Hurh Soomin Kang Jihwan Yoon Jong-Ik Hwang Derek T. Logan Hong-Rae Kim |
| author_sort | Hobin Lee |
| collection | DOAJ |
| description | USP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors. |
| format | Article |
| id | doaj-art-ebec408aa9f24fe6bfea554018e40007 |
| institution | Kabale University |
| 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-ebec408aa9f24fe6bfea554018e400072025-08-20T03:31:15ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2518191Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screeningHobin Lee0Sunghoon Hurh1Soomin Kang2Jihwan Yoon3Jong-Ik Hwang4Derek T. Logan5Hong-Rae Kim6Laboratory of Discovery Chemistry, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaGPCR & Signal Transduction Laboratory, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaLaboratory of Discovery Chemistry, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaLaboratory of Discovery Chemistry, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaGPCR & Signal Transduction Laboratory, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaSection for Biochemistry and Structural Biology, Centre for Molecular Protein Science, Department of Chemistry, Lund University, Lund, SwedenLaboratory of Discovery Chemistry, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaUSP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.https://www.tandfonline.com/doi/10.1080/14756366.2025.2518191Ubiquitin-specific proteaseinhibitorvirtual screeningprotein-ligand interactions |
| spellingShingle | Hobin Lee Sunghoon Hurh Soomin Kang Jihwan Yoon Jong-Ik Hwang Derek T. Logan Hong-Rae Kim Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening Journal of Enzyme Inhibition and Medicinal Chemistry Ubiquitin-specific protease inhibitor virtual screening protein-ligand interactions |
| title | Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening |
| title_full | Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening |
| title_fullStr | Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening |
| title_full_unstemmed | Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening |
| title_short | Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening |
| title_sort | identification of chemical scaffolds for targeting ubiquitin specific protease 11 usp11 through high throughput virtual screening |
| topic | Ubiquitin-specific protease inhibitor virtual screening protein-ligand interactions |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2518191 |
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