Structure-Based Design and Evaluation of Coumarin-Derived CDK4 Inhibitors for Non-Small Cell Lung Cancer: An...

Area of Science:

• Computational chemistry and drug discovery
• Oncology and molecular biology

Background:

• Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality globally.
• Dysregulation of the Cyclin-Dependent Kinase 4-Cyclin D3 complex drives NSCLC proliferation, making CDK4 a key therapeutic target.

Purpose of the Study:

• To identify novel coumarin-derived inhibitors of CDK4 for NSCLC treatment using an integrated computational approach.
• To evaluate the binding affinity, stability, and energetics of potential drug candidates.

Main Methods:

• A virtual library of 30,176 coumarin compounds was screened using pharmacokinetic filtering, molecular docking, and molecular dynamics (MD) simulations.
• The computational workflow included docking, MD simulations, and MM/PBSA binding free-energy calculations.
• Docking protocol validation was performed using the known inhibitor abemaciclib.

Main Results:

• Four lead compounds (4-methylesculetin, 3-acetamidocoumarin, esculetin, and daphnetin) were identified after filtering.
• 4-methylesculetin and 3-acetamidocoumarin showed high docking scores and stable interactions during MD simulations.
• MM/PBSA calculations confirmed favorable binding free energies for 4-methylesculetin and 3-acetamidocoumarin.

Conclusions:

• 4-methylesculetin was identified as the most promising computational lead candidate due to its balanced binding affinity and dynamic stability.
• Coumarin scaffolds represent a viable starting point for developing novel CDK4-targeted therapies for NSCLC.
• The study provides a strong computational basis for future experimental validation of these compounds.