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Virtual screening of novel alkaloids as potent inhibitors for G2032R-mutant ROS1 kinase in non-small-cell lung cancer
Shu-Chi Cho1, Yi-Wen Wang2, Chien-An Chu3
1Department of Horticulture, National Chiayi University, No.300 Syuefu Rd, Chiayi City, 60004, Taiwan (ROC).
Abstract:
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.
Insights
Novel alkaloids were computationally screened to find new inhibitors for drug-resistant ROS1-mutant non-small-cell lung cancer. Yibeinoside A shows promise as a selective inhibitor due to strong binding and favorable pharmacokinetics.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Drug resistance in ROS1-positive non-small-cell lung cancer (NSCLC) is a significant clinical challenge.
- The Gly2032Arg (G2032R) mutation in ROS1 is a key driver of resistance to targeted therapies.
- Identifying novel inhibitors is crucial for overcoming treatment resistance in NSCLC patients.
Purpose of the Study:
- To discover novel alkaloid inhibitors targeting the G2032R-mutant ROS1 protein.
- To evaluate the binding affinity, safety, and stability of potential drug candidates.
- To identify lead compounds for further development against resistant NSCLC.
Main Methods:
- Virtual screening of a library of 447 alkaloids using molecular docking.
- ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) property prediction for safety assessment.
- Molecular dynamics simulations and MM/PBSA calculations to assess binding stability and free energy.
Main Results:
- Yibeinoside A and vomicine were identified as top compounds with high binding affinity to G2032R-mutant ROS1.
- Yibeinoside A demonstrated superior predicted pharmacokinetic profiles compared to vomicine and lorlatinib.
- Molecular dynamics and MM/PBSA analyses confirmed the stability and favorable binding free energy of yibeinoside A and vomicine.
Conclusions:
- Yibeinoside A is a promising lead candidate for a selective inhibitor against G2032R-mutant ROS1.
- The compound exhibits balanced binding interactions and favorable predicted pharmacokinetics.
- Further development of yibeinoside A could offer a new therapeutic strategy for drug-resistant ROS1-positive NSCLC.
