Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang
{"title":"新型PLK1-PBD和PLK4-PB3双靶向抑制剂的发现:结构引导药效团建模、虚拟筛选、分子对接、分子动力学模拟和生物学评价。","authors":"Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang","doi":"10.1080/14756366.2025.2522810","DOIUrl":null,"url":null,"abstract":"<p><p>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 <b>1-5</b>) 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. <i>In vitro</i> cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-<b>2</b> showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: <i>K</i><sub>d</sub> = 8.02 ± 0.16 nM; PLK4-PB3: <i>K</i><sub>d</sub> = 11.32 ± 0.19 nM; IC<sub>50</sub> = 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.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2522810"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265104/pdf/","citationCount":"0","resultStr":"{\"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.\",\"authors\":\"Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang\",\"doi\":\"10.1080/14756366.2025.2522810\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <b>1-5</b>) 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. <i>In vitro</i> cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-<b>2</b> showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: <i>K</i><sub>d</sub> = 8.02 ± 0.16 nM; PLK4-PB3: <i>K</i><sub>d</sub> = 11.32 ± 0.19 nM; IC<sub>50</sub> = 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.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"40 1\",\"pages\":\"2522810\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265104/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2025.2522810\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2025.2522810","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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 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.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.