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<p>Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, emphasizing the urgent need for novel therapeutic agents with improved efficacy. Benzimidazole derivatives possess diverse pharmacological properties, including anticancer, antimicrobial, anti-inflammatory, and antioxidant activities; however, their precise mechanisms against LC remain unclear. In this study, an integrative in-silico approach combining network pharmacology (NP), molecular docking, molecular dynamics (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to elucidate the potential mechanisms of benzimidazole derivatives against LC. NP analysis identified key molecular targets associated with LC, while molecular docking with the best target Cyclin-Dependent Kinase 4 (CDK4) revealed that the metal-based benzimidazole derivative CuL1Br exhibited the binding affinity of -7.8&#xa0;kcal/mol, which is comparable to the control compound Trilaciclib (-8.5&#xa0;kcal/mol). MD simulations demonstrated the stability and compactness of the CuL1Br-CDK4 complex, with a root mean square deviation (RMSD) of 1.82 ± 0.25 Å, root mean square fluctuation (RMSF) of 1.03 ± 0.64 Å, radius of gyration (RoG) of 19.90 ± 0.12 Å, solvent-accessible surface area (SASA) of 14,562.82 ± 309.24 Ų, and hydrogen bonds (HB) of 136.18 ± 7.67. In comparison, the control complex showed RMSD = 2.02 ± 0.19 Å, RMSF = 1.02 ± 0.63 Å, RoG = 19.99 ± 0.13 Å, SASA = 14,631.79 ± 296.50 Ų, and HB = 132.31 ± 7.60, indicating that CuL1Br binding reduces structural fluctuations and enhances complex stability. Furthermore, principal component analysis (PCA), free energy landscape (FEL), and dynamic cross-correlation matrix (DCCM) analyses corroborate the stable and coordinated motions of the complex over the 200 ns trajectory. Additionally, MM/GBSA calculations showed favorable binding free energy (-17.70 ± 4.82&#xa0;kcal/mol), reflecting comparable and stable interactions. The favorable ADME characteristics of CuL1Br highlight its promising drug-like profile and support its potential for further pharmacological investigation. Collectively, these results highlight CuL1Br as a promising CDK4 inhibitor with significant therapeutic potential against LC, providing a foundation for further experimental validation and targeted therapy development.</p>

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Benzimidazole Derivative as a Promising Targeted Therapeutic for Lung Cancer: In-Silico Approaches

  • 期刊论文

  • 发表日期：

    2026年4月10日

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  • Roney Miah,
  • Abdul Rashid Issahaku,
  • Md. Nazim Uddin,
  • Muhamad Azwan Hamali,
  • Md Mahfuz Miah,
  • Karimah Kassim,
  • Anke Wilhelm,
  • Mohd Fadhlizil Fasihi Mohd Aluwi

摘要

Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, emphasizing the urgent need for novel therapeutic agents with improved efficacy. Benzimidazole derivatives possess diverse pharmacological properties, including anticancer, antimicrobial, anti-inflammatory, and antioxidant activities; however, their precise mechanisms against LC remain unclear. In this study, an integrative in-silico approach combining network pharmacology (NP), molecular docking, molecular dynamics (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to elucidate the potential mechanisms of benzimidazole derivatives against LC. NP analysis identified key molecular targets associated with LC, while molecular docking with the best target Cyclin-Dependent Kinase 4 (CDK4) revealed that the metal-based benzimidazole derivative CuL1Br exhibited the binding affinity of -7.8 kcal/mol, which is comparable to the control compound Trilaciclib (-8.5 kcal/mol). MD simulations demonstrated the stability and compactness of the CuL1Br-CDK4 complex, with a root mean square deviation (RMSD) of 1.82 ± 0.25 Å, root mean square fluctuation (RMSF) of 1.03 ± 0.64 Å, radius of gyration (RoG) of 19.90 ± 0.12 Å, solvent-accessible surface area (SASA) of 14,562.82 ± 309.24 Ų, and hydrogen bonds (HB) of 136.18 ± 7.67. In comparison, the control complex showed RMSD = 2.02 ± 0.19 Å, RMSF = 1.02 ± 0.63 Å, RoG = 19.99 ± 0.13 Å, SASA = 14,631.79 ± 296.50 Ų, and HB = 132.31 ± 7.60, indicating that CuL1Br binding reduces structural fluctuations and enhances complex stability. Furthermore, principal component analysis (PCA), free energy landscape (FEL), and dynamic cross-correlation matrix (DCCM) analyses corroborate the stable and coordinated motions of the complex over the 200 ns trajectory. Additionally, MM/GBSA calculations showed favorable binding free energy (-17.70 ± 4.82 kcal/mol), reflecting comparable and stable interactions. The favorable ADME characteristics of CuL1Br highlight its promising drug-like profile and support its potential for further pharmacological investigation. Collectively, these results highlight CuL1Br as a promising CDK4 inhibitor with significant therapeutic potential against LC, providing a foundation for further experimental validation and targeted therapy development.