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Natural product-derived ALK inhibitors for treating ALK-driven lung cancers: an in silico study
Saud O Alshammari1, Qamar A Alshammari2,3
1Department of Pharmacognosy and Alternative Medicine, College of Pharmacy, Northern Border University, Rafha, 76321, Saudi Arabia. saud.o.alshammari@nbu.edu.sa.
Abstract:
Anaplastic lymphoma kinase (ALK)-driven lung cancer represents a critical therapeutic target, demanding innovative approaches for the identification of effective inhibitors. Anaplastic lymphoma kinase (ALK), a key protein involved in the pathogenesis of ALK-driven lung cancers, has been the focus of extensive drug discovery efforts. This study employed a comprehensive computational drug discovery approach, integrating virtual screening with the Lipinski filter, re-docking, molecular dynamics (MD) simulations, and free energy calculations to identify potential inhibitors from a natural compound library. Utilizing the MTiOpenScreen web server, we screened for compounds that exhibit favorable interactions with ALK, resulting in 1227 compounds with virtual screening scores ranging from - 10.2 to - 3.7 kcal/mol. Subsequent re-docking of three selected compounds (ZINC000059779788, ZINC000043552589, and ZINC000003594862) and one reference compound against ALK yielded docking scores - 10.4, - 10.2, - 10.2, and - 10.1 kcal/mol, respectively. These compounds demonstrated promising interactions with ALK, suggesting potential inhibitory effects. Advanced analyses, including MD simulation and binding free energy calculations, further supported the potential efficacy of these compounds. MD simulations, particularly the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses, revealed that compounds ZINC000059779788 and ZINC000003594862 achieved better stability compared to compound ZINC000043552589. These stable conformations suggest effective binding over time. Free energy calculations using the MM/GBSA method showed that ZINC000059779788 had the most favorable binding energy, indicating a strong and stable interaction with the ALK protein. The promising computational findings from this study emphasize the necessity for additional experimental testing to verify the therapeutic efficacy of these natural compounds for treating lung cancers.
Insights
This study computationally identified natural compounds as potential inhibitors for anaplastic lymphoma kinase (ALK)-driven lung cancer. Promising candidates like ZINC000059779788 showed stable binding, warranting further experimental validation.
Area of Science:
- Computational chemistry and drug discovery
- Oncology and molecular biology
- Pharmacology and natural products
Background:
- Anaplastic lymphoma kinase (ALK)-driven lung cancer is a significant therapeutic challenge.
- Identifying novel ALK inhibitors is crucial for effective lung cancer treatment.
- Natural compounds offer a promising source for drug discovery.
Purpose of the Study:
- To computationally identify potential natural inhibitors of anaplastic lymphoma kinase (ALK).
- To screen a natural compound library for compounds with favorable interactions with ALK.
- To validate the binding stability and energy of top candidate compounds using advanced computational methods.
Main Methods:
- Virtual screening of a natural compound library using the MTiOpenScreen web server.
- Lipinski filter application and re-docking of selected compounds against ALK.
- Molecular dynamics (MD) simulations to assess binding stability (RMSD, RMSF).
- MM/GBSA calculations for binding free energy estimation.
Main Results:
- 1227 compounds showed favorable virtual screening scores against ALK.
- Three selected compounds (ZINC000059779788, ZINC000043552589, ZINC000003594862) exhibited strong docking scores.
- MD simulations indicated ZINC000059779788 and ZINC000003594862 possess superior binding stability.
- MM/GBSA calculations identified ZINC000059779788 as having the most favorable binding energy.
Conclusions:
- Computational methods successfully identified potential natural inhibitors for ALK-driven lung cancer.
- ZINC000059779788 demonstrates significant potential as a stable ALK inhibitor.
- Further experimental validation is necessary to confirm the therapeutic efficacy of these compounds.
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