Structure-Based Design and Evaluation of Coumarin-Derived CDK4 Inhibitors for Non-Small Cell Lung Cancer: An
N M Arulmozhi1, Thiyagarajan G2
1Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai, 600113, India.
Abstract:
Lung cancer remains the leading cause of cancer related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of cases. Dysregulation of the Cyclin-Dependent Kinase 4-Cyclin D3 complex promotes uncontrolled cell proliferation and represents an attractive therapeutic target in NSCLC. In this study, an integrated computational workflow comprising pharmacokinetic filtering, molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding free-energy calculations was employed to identify putative coumarin-derived CDK4 inhibitor candidates from a virtual library of 30,176 compounds. The docking protocol was validated using the co-crystallized CDK4/6 inhibitor abemaciclib, yielding a redocking RMSD of 1.38 Å and a docking score of - 9.86 kcal·mol⁻1. Following Lipinski and QikProp filtering, four lead compounds, 4-methylesculetin, 3-acetamidocoumarin, esculetin, and daphnetin, were selected for detailed investigation. Docking analysis identified 4-methylesculetin (- 8.63 kcal·mol⁻1) and 3-acetamidocoumarin (- 9.10 kcal·mol⁻1) as the top-ranked ligands. Triplicate 200 ns MD simulations demonstrated stable protein-ligand complexes characterized by persistent active-site interactions, favorable conformational stability, and sustained hydrogen-bond occupancy. MM/PBSA calculations further supported the favorable binding energetics of 4-methylesculetin (ΔG_bind = - 22.99 ± 3.31 kcal·mol⁻1) and 3-acetamidocoumarin (ΔG_bind = - 22.36 ± 2.07 kcal·mol⁻1). Integrated evaluation of docking affinity, dynamic stability, hydrogen-bond persistence, binding free-energy profiles, and conformational behavior identified 4-methylesculetin as the most balanced computational lead candidate. Collectively, these findings establish coumarin-derived scaffolds as promising starting points for the development of next-generation CDK4-targeted therapeutics and provide a strong computational foundation for future experimental validation in NSCLC.
Insights
Computational methods identified coumarin derivatives as potential inhibitors for Cyclin-Dependent Kinase 4 (CDK4) in non-small cell lung cancer (NSCLC). 4-methylesculetin emerged as a promising lead compound for developing new NSCLC therapeutics.
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.
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