Hong Zhou, Lixia Guan, Guoqiang Lin, Xiaotian Yang, Xingxia Zhang, Yejun Si, Yanming Zhang, Juan Chen
{"title":"靶向PLK1 polo-box结构域的新型有效肽抑制剂的鉴定:基于结构的药效团建模、虚拟筛选、分子对接、分子动力学研究和生物学评价。","authors":"Hong Zhou, Lixia Guan, Guoqiang Lin, Xiaotian Yang, Xingxia Zhang, Yejun Si, Yanming Zhang, Juan Chen","doi":"10.1080/14756366.2025.2563601","DOIUrl":null,"url":null,"abstract":"<p><p>Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1-5 had strong binding affinity for PLK1, especially PL-1 (<i>K</i><sub>d</sub> = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC<sub>50</sub> = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2563601"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486458/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identification of novel potent peptide inhibitors targeting the polo-box domain of PLK1: structure-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics study and biological evaluation.\",\"authors\":\"Hong Zhou, Lixia Guan, Guoqiang Lin, Xiaotian Yang, Xingxia Zhang, Yejun Si, Yanming Zhang, Juan Chen\",\"doi\":\"10.1080/14756366.2025.2563601\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1-5 had strong binding affinity for PLK1, especially PL-1 (<i>K</i><sub>d</sub> = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC<sub>50</sub> = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"40 1\",\"pages\":\"2563601\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486458/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2025.2563601\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/9/30 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/10.1080/14756366.2025.2563601","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Identification of novel potent peptide inhibitors targeting the polo-box domain of PLK1: structure-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics study and biological evaluation.
Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1-5 had strong binding affinity for PLK1, especially PL-1 (Kd = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC50 = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.
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.