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Published on: May 20, 2015
Discovery of Small Molecule Inhibitors against Polo-Like Kinase 1 Targeting Breast Cancer
Gayatri Munieswaran1, Venkatraman Manickam1
1School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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.
Insights
Silymarin effectively inhibits polo-like kinase-1 (PLK1) in breast cancer cells. This study utilized computational methods and in vitro testing to identify silymarin as a promising therapeutic agent targeting PLK1, a key driver of cancer proliferation.
Area of Science:
- Oncology
- Computational Chemistry
- Pharmacology
Background:
- Polo-like kinase-1 (PLK1) is crucial for cell cycle regulation and proliferation.
- Dysregulated PLK1 activity drives oncogenic pathways, contributing to breast cancer development.
- Targeting the PLK1 kinase domain offers a strategy to prevent tumor growth.
Purpose of the Study:
- To identify novel small molecule inhibitors of PLK1 using a machine learning approach.
- To evaluate the binding affinity and stability of potential inhibitors with PLK1.
- To assess the in vitro efficacy of the identified inhibitor in breast cancer cells.
Main Methods:
- Machine learning model developed for screening small molecules against PLK1.
- Molecular docking and dynamic simulations to assess binding affinity and complex stability.
- In vitro evaluation using the SKBR3 breast cancer cell line.
Main Results:
- Silymarin exhibited superior binding energy (-9.2 Kcal/mol) and stability with PLK1 compared to other molecules.
- Molecular dynamics simulations confirmed silymarin's stable, compact, and less flexible interaction with PLK1.
- Silymarin demonstrated significant binding free energy (-13.25 kcal/mol) and an IC50 of 95.76 μg/mL, inducing apoptosis in SKBR3 cells.
Conclusions:
- Silymarin effectively inhibits PLK1, a potential oncogenic target in breast cancer.
- Computational and in vitro studies validate silymarin as a potent PLK1 inhibitor.
- Silymarin represents a potential alternative therapeutic agent for PLK1-driven cancers, including HER2-positive breast cancer.
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