Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides
Background: Cancer remains an awful challenge, despite years of targeting proteins to control its relentless growth and spread. Fungal metabolites, a treasure of natural chemicals, offer a glimmer of hope. Telomeres, the cellular “caps,” are a focal point in cancer research. This study explores the...
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Elsevier
2025-03-01
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| Series: | Journal of Genetic Engineering and Biotechnology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1687157X24001574 |
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| author | Gourav Choudhir Sushil Kumar Mohammad Shahid Anas Shamsi Asimul Islam |
| author_facet | Gourav Choudhir Sushil Kumar Mohammad Shahid Anas Shamsi Asimul Islam |
| author_sort | Gourav Choudhir |
| collection | DOAJ |
| description | Background: Cancer remains an awful challenge, despite years of targeting proteins to control its relentless growth and spread. Fungal metabolites, a treasure of natural chemicals, offer a glimmer of hope. Telomeres, the cellular “caps,” are a focal point in cancer research. This study explores the potential of stabilizing Telomeric Repeats-containing RNA G-quadruplex (TERRA G4) structures within telomeres. This stabilization could block telomerase, the enzyme that repairs telomeres, and potentially trigger cancer cell death. Agonodepsides A and B, two promising fungal metabolites, were chosen to investigate this exciting possibility. Methods: Agonodepside A and B were initially screened for drug likeness employing SwissAdme. AutoDock Vina was used for molecular docking, and ligands and TERRA G4 were prepared using PyRx and MGL tool. Discovery Studio software was utilized for the visualization of interactions between ligands and TERRA G4. For validation of docking results MD simulation for control and complexes was carried out for 250 ns and trajectories were analyzed for different parameters. MMPBSA was used to calculate binding free energy for control and complexes. To find the stable and lower energy states of complexes in comparison to control principal component analysis (PCA) and free energy landscape (FEL) were conducted. Results: Absorption, distribution, metabolism, and excretion (ADME) of both agonodepsides followed Lipinski’s rule of five with zero violation. Molecular docking revealed several key interactions including hydrogen bonds, van der Waals interactions, π-alkyl and π-anion. MD simulation revealed that Agonodepside A interact with TERRA G4 and stabilize it while Agonodepside B interactions were transient. The MMPBSA binding free energy calculation, PCA and free energy landscapes supported the docking and MD simulation results. Conclusion: Lichenized fungi produce agonodepsides A and B, may fight cancer by targeting telomeres. Agonodepside A binds more strongly to telomeres than B, potentially blocking enzyme telomerase. Further studies are required to validate these findings and evaluate potential safety concerns. |
| format | Article |
| id | doaj-art-64a9cb201a9a44bb99ad4f8453c6b2b8 |
| institution | DOAJ |
| issn | 1687-157X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Journal of Genetic Engineering and Biotechnology |
| spelling | doaj-art-64a9cb201a9a44bb99ad4f8453c6b2b82025-08-20T02:47:32ZengElsevierJournal of Genetic Engineering and Biotechnology1687-157X2025-03-0123110045410.1016/j.jgeb.2024.100454Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsidesGourav Choudhir0Sushil Kumar1Mohammad Shahid2Anas Shamsi3Asimul Islam4Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, IndiaDepartment of Botany, Shaheed Mangal Pandey Govt. Girls PG College, Meerut 250002, IndiaDepartment of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi ArabiaCenter for Medical and Bio-Allied Health Sciences Research, Ajman University, United Arab Emirates; Corresponding author at: Center for Medical and Bio-Allied Health Sciences Research, Ajman University, United Arab EmiratesCentre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Corresponding author at: Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.Background: Cancer remains an awful challenge, despite years of targeting proteins to control its relentless growth and spread. Fungal metabolites, a treasure of natural chemicals, offer a glimmer of hope. Telomeres, the cellular “caps,” are a focal point in cancer research. This study explores the potential of stabilizing Telomeric Repeats-containing RNA G-quadruplex (TERRA G4) structures within telomeres. This stabilization could block telomerase, the enzyme that repairs telomeres, and potentially trigger cancer cell death. Agonodepsides A and B, two promising fungal metabolites, were chosen to investigate this exciting possibility. Methods: Agonodepside A and B were initially screened for drug likeness employing SwissAdme. AutoDock Vina was used for molecular docking, and ligands and TERRA G4 were prepared using PyRx and MGL tool. Discovery Studio software was utilized for the visualization of interactions between ligands and TERRA G4. For validation of docking results MD simulation for control and complexes was carried out for 250 ns and trajectories were analyzed for different parameters. MMPBSA was used to calculate binding free energy for control and complexes. To find the stable and lower energy states of complexes in comparison to control principal component analysis (PCA) and free energy landscape (FEL) were conducted. Results: Absorption, distribution, metabolism, and excretion (ADME) of both agonodepsides followed Lipinski’s rule of five with zero violation. Molecular docking revealed several key interactions including hydrogen bonds, van der Waals interactions, π-alkyl and π-anion. MD simulation revealed that Agonodepside A interact with TERRA G4 and stabilize it while Agonodepside B interactions were transient. The MMPBSA binding free energy calculation, PCA and free energy landscapes supported the docking and MD simulation results. Conclusion: Lichenized fungi produce agonodepsides A and B, may fight cancer by targeting telomeres. Agonodepside A binds more strongly to telomeres than B, potentially blocking enzyme telomerase. Further studies are required to validate these findings and evaluate potential safety concerns.http://www.sciencedirect.com/science/article/pii/S1687157X24001574TelomeresGenome StabilityFungal MetabolitesMolecular Docking and SimulationPrincipal Component AnalysisFree Energy Landscapes |
| spellingShingle | Gourav Choudhir Sushil Kumar Mohammad Shahid Anas Shamsi Asimul Islam Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides Journal of Genetic Engineering and Biotechnology Telomeres Genome Stability Fungal Metabolites Molecular Docking and Simulation Principal Component Analysis Free Energy Landscapes |
| title | Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides |
| title_full | Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides |
| title_fullStr | Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides |
| title_full_unstemmed | Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides |
| title_short | Telomeric RNA quadruplexes as targets for cancer prevention: The therapeutic potential of agonodepsides |
| title_sort | telomeric rna quadruplexes as targets for cancer prevention the therapeutic potential of agonodepsides |
| topic | Telomeres Genome Stability Fungal Metabolites Molecular Docking and Simulation Principal Component Analysis Free Energy Landscapes |
| url | http://www.sciencedirect.com/science/article/pii/S1687157X24001574 |
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