Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Chem. 2018 Dec;81:278-288. doi: 10.1016/j.bioorg.2018.08.030. Epub 2018 Aug 23.
A series of non-peptide inhibitors targeting the polo-box domain (PBD) of polo-like kinase 1 (Plk1) was designed based on the potent and selective minimal tripeptide Plk1 PBD inhibitor. Seven compounds were designed, synthesized and evaluated for fluorescence polarization (FP) assay. The most promising compound 10 bound to Plk1 PBD with IC of 3.37 μM and had no binding to Plk2 PBD or Plk3 PBD at 100 μM. Molecular docking study was performed and possible binding mode was proposed. MM/GBSA binding free energy calculation were in agreement with the observed experimental results. These novel non-peptide selective Plk1 PBD inhibitors provided new lead compounds for further optimization.
基于强效且选择性的最小三肽 Polo 样激酶 1（Plk1）PBD 抑制剂，设计了一系列针对 Polo 样激酶 1（Plk1）PBD 的非肽类抑制剂。设计、合成了 7 种化合物，并进行了荧光偏振（FP）测定。最有前途的化合物 10 与 Plk1 PBD 的 IC 为 3.37 μM，在 100 μM 时与 Plk2 PBD 或 Plk3 PBD 无结合。进行了分子对接研究，并提出了可能的结合模式。MM/GBSA 结合自由能计算与观察到的实验结果一致。这些新型非肽类选择性 Plk1 PBD 抑制剂为进一步优化提供了新的先导化合物。
