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<p>Osteosarcoma, the most common primary bone malignancy in children and adolescents, has driven extensive research into its molecular drivers and pathways. Here, we conducted an in silico investigation of six marine-derived alkaloids targeting four critical proteins: estrogen receptor alpha (ERα), bone morphogenetic protein 2 (BMP-2), heat shock protein 90 (Hsp90), and serine/threonine-protein kinase (PIM1) in the osteosarcoma SaOS2 cell line. The compounds assessed were Coscinamides A, B, and C, Leucettamine B, Dispacamide A, and Eudistomin Y1. Molecular docking via AutoDock Vina (UCSF Chimera) identified Eudistomin Y1 and Coscinamide A as the most promising candidates. These underwent 100 ns molecular dynamics simulations with Desmond to evaluate stability and interactions. Eudistomin Y1 showed consistently favorable dynamics across ERα, BMP-2, and PIM1, maintaining low RMSD (~ 2–3 Å), compact conformations, and strong hydrophobic and electrostatic contacts with low solvent exposure. Coscinamide A, docked to Hsp90, exhibited stable binding with diversified interactions closely resembling the reference ligand. Additional metrics, including solvent-accessible surface area, radius of gyration, molecular surface area, and polar surface area, confirmed structural stability. ADMET predictions suggested favorable pharmacokinetic and toxicity profiles. CLC-Pred cytotoxicity analysis indicated Eudistomin Y1 has predicted activity against glioblastoma, adrenal carcinoma, and lung carcinoma cell lines, while Coscinamide A showed potential activity against breast carcinoma. STRING-based protein-protein interaction network analysis highlighted relevant functional associations reinforcing the therapeutic relevance of these targets. Overall, these findings support Eudistomin Y1 as a promising multitarget β-carboline scaffold and Coscinamide A as a potential Hsp90 modulator warranting further validation.</p>

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Marine-derived alkaloids as multitarget anticancer agents: an in silico exploration of osteosarcoma inhibition through docking, dynamics, cytotoxicity, and protein interaction networks

  • 期刊论文

  • 发表日期：

    2026年3月26日

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  • Abderahmane Linani,
  • Leila Bou-Salah,
  • Anis Khelifa,
  • Khouloud Tamimount,
  • Khedidja Benarous,
  • Alaeddine Kaouka

摘要

Osteosarcoma, the most common primary bone malignancy in children and adolescents, has driven extensive research into its molecular drivers and pathways. Here, we conducted an in silico investigation of six marine-derived alkaloids targeting four critical proteins: estrogen receptor alpha (ERα), bone morphogenetic protein 2 (BMP-2), heat shock protein 90 (Hsp90), and serine/threonine-protein kinase (PIM1) in the osteosarcoma SaOS2 cell line. The compounds assessed were Coscinamides A, B, and C, Leucettamine B, Dispacamide A, and Eudistomin Y1. Molecular docking via AutoDock Vina (UCSF Chimera) identified Eudistomin Y1 and Coscinamide A as the most promising candidates. These underwent 100 ns molecular dynamics simulations with Desmond to evaluate stability and interactions. Eudistomin Y1 showed consistently favorable dynamics across ERα, BMP-2, and PIM1, maintaining low RMSD (~ 2–3 Å), compact conformations, and strong hydrophobic and electrostatic contacts with low solvent exposure. Coscinamide A, docked to Hsp90, exhibited stable binding with diversified interactions closely resembling the reference ligand. Additional metrics, including solvent-accessible surface area, radius of gyration, molecular surface area, and polar surface area, confirmed structural stability. ADMET predictions suggested favorable pharmacokinetic and toxicity profiles. CLC-Pred cytotoxicity analysis indicated Eudistomin Y1 has predicted activity against glioblastoma, adrenal carcinoma, and lung carcinoma cell lines, while Coscinamide A showed potential activity against breast carcinoma. STRING-based protein-protein interaction network analysis highlighted relevant functional associations reinforcing the therapeutic relevance of these targets. Overall, these findings support Eudistomin Y1 as a promising multitarget β-carboline scaffold and Coscinamide A as a potential Hsp90 modulator warranting further validation.