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<p>The Gly2032Arg (G2032R) point mutation in proto-oncogene tyrosine-protein kinase 1 (ROS1) is one of the predominant factors of drug resistance to targeted therapies in patients with ROS1 fusion-positive non–small-cell lung cancer (NSCLC). This study aimed to identify novel inhibitors from a library of alkaloids (447 compounds) using computational approaches. Molecular docking-based virtual screening was performed to identify promising compounds, followed by ADMET property prediction and molecular dynamics simulations to assess their safety and stability. The top compounds identified were yibeinoside A and vomicine, which exhibited high binding affinities to the G2032R-mutant ROS1 protein. ADMET analysis indicated that yibeinoside A possessed better predicted pharmacokinetic profiles than vomicine and the positive control, lorlatinib. Molecular dynamics simulations demonstrated that yibeinoside A formed a highly stable complex with stable root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA) values. Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) calculations further confirmed that yibeinoside A and vomicine had better binding free energies than lorlatinib. Collectively, these findings suggest that yibeinoside A, with its balanced binding interactions and favorable predicted pharmacokinetic profile, is a promising lead candidate for further development as a selective inhibitor against G2032R-mutant ROS1.</p>

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Virtual screening of novel alkaloids as potent inhibitors for G2032R-mutant ROS1 kinase in non-small-cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Shu-Chi Cho,
  • Yi-Wen Wang,
  • Chien-An Chu,
  • Ming-Chih Huang,
  • Chung-Ta Lee

摘要

The Gly2032Arg (G2032R) point mutation in proto-oncogene tyrosine-protein kinase 1 (ROS1) is one of the predominant factors of drug resistance to targeted therapies in patients with ROS1 fusion-positive non–small-cell lung cancer (NSCLC). This study aimed to identify novel inhibitors from a library of alkaloids (447 compounds) using computational approaches. Molecular docking-based virtual screening was performed to identify promising compounds, followed by ADMET property prediction and molecular dynamics simulations to assess their safety and stability. The top compounds identified were yibeinoside A and vomicine, which exhibited high binding affinities to the G2032R-mutant ROS1 protein. ADMET analysis indicated that yibeinoside A possessed better predicted pharmacokinetic profiles than vomicine and the positive control, lorlatinib. Molecular dynamics simulations demonstrated that yibeinoside A formed a highly stable complex with stable root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA) values. Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) calculations further confirmed that yibeinoside A and vomicine had better binding free energies than lorlatinib. Collectively, these findings suggest that yibeinoside A, with its balanced binding interactions and favorable predicted pharmacokinetic profile, is a promising lead candidate for further development as a selective inhibitor against G2032R-mutant ROS1.