基于人工智能的PLK1 PBD新型抑制剂的筛选  

Screening of Novel Inhibitors of PLK1 PBD Based on Artificial Intelligence

作　　者：朱艳娟 刘小倩 冯大为 王璐琪 刘钰杭 曹琳慧 芦静 ZHU Yanjuan;LIU Xiaoqian;FENG Dawei;WANG Luqi;LIU Yuhang;CAO Linhui;LU Jing(School of Pharmacy,Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China)

机构地区：[1]烟台大学药学院,分子药理和药物评价教育部重点实验室(烟台大学),新型制剂与生物技术药物研究山东省高校协同创新中心,山东烟台264005

出　　处：《烟台大学学报(自然科学与工程版)》2025年第1期92-100,共9页Journal of Yantai University(Natural Science and Engineering Edition)

基　　金：泰山学者项目(主持人:赵克浩)。

摘　　要：使用基于化合物性质预测的COVIDVS模型和基于蛋白-化合物相互作用预测的RTMScore模型对具有超140万个化合物进行虚拟筛选,并根据在结合口袋(酪氨酸结合口袋和含有H538、K540的磷酸肽结合口袋)的结合模式选择靶向PLK1 PBD的新型小分子抑制剂。通过MTT法测定化合物抑制肿瘤细胞增殖的活性,然后进行细胞克隆实验和细胞划痕实验,检测化合物抗HCT116肿瘤细胞增殖、迁移的能力;最后通过分子动力学模拟和细胞热转移分析实验验证化合物的靶向性。结果表明,从COVIDVS预测打分为1且RTMScore打分≥80的2291个化合物中选择的5个化合物,其中化合物1在10μmol·L^(-1)时对HCT116肿瘤细胞增殖的抑制率超过60%,IC 50为7.24μmol·L^(-1),化合物1抑制HCT116细胞克隆的形成和HCT116肿瘤细胞的迁移;分子模拟实验显示化合物1与PLK1 PBD结构域结合,并通过细胞热转移实验证实。The COVIDVS model,based on compound property prediction,and the RTMScore model,based on protein-compound interaction prediction,were used for virtual screening of more than 1.4 million compounds.New small molecule inhibitors targeting PLK1 PBD were selected according to their binding patterns in binding pockets(tyrosine binding pockets and phosphopeptide-binding pockets containing H538 and K540).The inhibitory activity on HCT116 tumor cells was determined by MTT assay,and the anti-proliferation and migration ability of HCT116 tumor cells were assessed by cell cloning and cell scratch experiments.Finally,the targeting properties of the compounds were verified by molecular dynamics simulation and cell heat transfer analysis experiments.The results showed that 5 compounds were selected from the 2291 compounds with a COVIDVS predicted score of 1 and RTMScore≥80,among which compound 1 had an inhibition rate of more than 60%on HCT116 tumor cells at 10μmol·L^(-1),with an IC 50 of 7.24μmol·L^(-1).Compound 1 inhibited the formation of HCT116 cell clones and the migration of HCT116 tumor cells.Molecular simulations showed that compound 1 could bind to the PLK1 PBD domain,which was confirmed by the cell heat transfer experiments.

关 键 词：PLK1 PBD结构域 小分子抑制剂 活性测试 

分 类 号：R914.2[医药卫生—药物化学]