Identification of Natural Flavonoids Targeting PLK-1 as Potential Anti-Metastatic Agents: A Computational Approach

Area of Science:

• Computational chemistry
• Drug discovery
• Biochemistry

Background:

• Polo-Like Kinase-1 (PLK-1) is crucial in mitosis and frequently overexpressed in cancer, making it a target for anticancer therapies.
• Flavonoids are natural compounds with potential medicinal properties, including anticancer activity.
• Targeting PLK-1 is a promising strategy for developing novel antitumor drugs, particularly for metastatic cancers.

Purpose of the Study:

• To predict the inhibitory activity of natural flavonoids against the PLK-1 enzyme using integrated *in silico* approaches.
• To identify potential flavonoid-based anticancer agents through virtual screening and molecular docking.
• To elucidate the structure-activity relationships governing flavonoid interactions with PLK-1.

Main Methods:

• Development of classification models (linear discriminant analysis, multilayer perceptron) for virtual screening.
• Molecular docking to assess binding modes and interactions with the PLK-1 catalytic domain.
• Molecular dynamics simulations and MM/GBSA calculations to analyze binding stability and thermodynamics.

Main Results:

• Four natural compounds were identified as potential antitumor drugs via virtual screening with >80% accuracy.
• Myricetin exhibited the most favorable computational profile, including high virtual-screening scores and favorable MM/GBSA estimates.
• The hydroxylation pattern of ring B in flavonols significantly influences electrostatic interactions and water-mediated networks with PLK-1.

Conclusions:

• Integrated *in silico* strategies provide a robust framework for identifying promising drug candidates.
• Myricetin is prioritized for experimental evaluation as a potential PLK-1 inhibitor.
• This approach reduces time and cost in early-stage drug development for anticancer agents.