Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation
Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides 1–5) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via p...
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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/10.1080/14756366.2025.2522810 |
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| author | Changhao Zhao Hanying Wu Huajing Liu Hui Dong Miao-Miao Niu Kun Shi Fengzhen Wang |
| author_facet | Changhao Zhao Hanying Wu Huajing Liu Hui Dong Miao-Miao Niu Kun Shi Fengzhen Wang |
| author_sort | Changhao Zhao |
| collection | DOAJ |
| description | Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides 1–5) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. In vitro cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-2 showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: Kd = 8.02 ± 0.16 nM; PLK4-PB3: Kd = 11.32 ± 0.19 nM; IC50 = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy. |
| format | Article |
| id | doaj-art-fd75de7aae5d4781bbbd9e7d2c779e4a |
| institution | DOAJ |
| 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-fd75de7aae5d4781bbbd9e7d2c779e4a2025-08-20T03:13:07ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2522810Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluationChanghao Zhao0Hanying Wu1Huajing Liu2Hui Dong3Miao-Miao Niu4Kun Shi5Fengzhen Wang6Department of Pharmacy, Fengxian People’s Hospital, Xuzhou, Jiangsu, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, Jiangsu, ChinaDepartment of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, Jiangsu, ChinaDepartment of Orthopedics, Xuzhou Central Hospital, Xuzhou, Jiangsu, ChinaDepartment of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaAberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides 1–5) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. In vitro cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-2 showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: Kd = 8.02 ± 0.16 nM; PLK4-PB3: Kd = 11.32 ± 0.19 nM; IC50 = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy.https://www.tandfonline.com/doi/10.1080/14756366.2025.2522810Polo-box domain of polo-like kinase 1 (PLK1-PBD)polo-box 3 of PLK4 (PLK4-PB3)pharmacophore screeningdocking screening |
| spellingShingle | Changhao Zhao Hanying Wu Huajing Liu Hui Dong Miao-Miao Niu Kun Shi Fengzhen Wang Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation Journal of Enzyme Inhibition and Medicinal Chemistry Polo-box domain of polo-like kinase 1 (PLK1-PBD) polo-box 3 of PLK4 (PLK4-PB3) pharmacophore screening docking screening |
| title | Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation |
| title_full | Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation |
| title_fullStr | Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation |
| title_full_unstemmed | Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation |
| title_short | Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation |
| title_sort | discovery of novel dual targeting inhibitors against plk1 pbd and plk4 pb3 structure guided pharmacophore modelling virtual screening molecular docking molecular dynamics simulation and biological evaluation |
| topic | Polo-box domain of polo-like kinase 1 (PLK1-PBD) polo-box 3 of PLK4 (PLK4-PB3) pharmacophore screening docking screening |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2522810 |
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