Discovery of Small Molecule Inhibitors against Polo-Like Kinase 1 Targeting Breast Cancer.

[INTRODUCTION] The polo-like kinase-1 (PLK1) plays a significant role in cell cycle regulation and proliferation; upon dysregulation, PLK1 activates different oncogenic pathways that lead to breast cancer. Therefore, targeting the PLK1 protein on the kinase domain prevents the possibility of tumor development.

[METHODS] A machine learning model was developed to screen small molecules against PLK1 using a cancer bioassay dataset. The binding affinity and structural integrity of the complex were assessed using molecular docking and dynamic studies. In vitro evaluation was then performed for the screened compound against the SKBR3 cell line.

[RESULTS] The research findings highlighted the silymarin flavonoid to have a greater binding energy with PLK1 (-9.2 Kcal/mol) than other molecules (above -8.5 Kcal/mol). Additionally, the molecular dynamics simulation showed silymarin to be more stable, less flexible, and more compact with PLK1. Further, the binding free energy revealed silymarin to be more stable with PLK1 (-13.25 kcal/mol) than volasertib (-2.87 kcal/mol). The IC50 value of silymarin was found to be 95.76 μg/mL, inducing apoptosis on the SKBR3 cell line.

[DISCUSSION] Despite PLK1 being predicted as a potential oncogenic target, the treatment choices were limited. A cheminformatics approach was utilized for screening inhibitors against PLK1. The in silico and in vitro evaluations indicated that silymarin effectively inhibited the PLK1 protein in breast cancer.

[CONCLUSION] These research findings established silymarin as a potential alternative drug targeting PLK1, which is highly expressed in HER2-positive breast cancer, and modulates the oncogenic processes not just in breast cancer, but also in other cancers.