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<p>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&#xa0;Å and a docking score of − 9.86&#xa0;kcal·mol⁻<sup>1</sup>. 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&#xa0;kcal·mol⁻<sup>1</sup>) and 3-acetamidocoumarin (− 9.10&#xa0;kcal·mol⁻<sup>1</sup>) as the top-ranked ligands. Triplicate 200&#xa0;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&#xa0;kcal·mol⁻<sup>1</sup>) and 3-acetamidocoumarin (ΔG_bind = − 22.36 ± 2.07&#xa0;kcal·mol⁻<sup>1</sup>). 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • N. M. Arulmozhi,
  • Thiyagarajan G

摘要

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.

Graphical Abstract