Decoding the molecular mechanism via systems biology-based insights into neoschaftoside from Ailanthus altissima
Sachin Gudasi1, Dileep Kumar2, Shashank Tewari2
1Department of Pharmacognosy, KLE College of Pharmacy, KLE Academy of Higher Education and Research, Belagavi, Karnataka, 590010, India.
Abstract:
The epidermal growth factor receptor (EGFR) is a critical regulator of multiple oncogenic signaling cascades, including MAPK, PI3K/AKT/mTOR, and JAK-STAT pathways, which collectively contribute to enhanced proliferation, angiogenesis, and resistance to apoptosis in cancer. Aberrant EGFR activation has been strongly associated with tumor progression and therapeutic resistance, underscoring its importance as a molecular target for anticancer interventions. Ailanthus altissima (A. altissima), is known for its broad-spectrum anticancer potential although the underlying mechanism has not yet been clearly defined. Therefore, in present study, bioactive constituents of A. altissima were systematically analyzed for their ability to modulate proteins implicated in cancer pathogenesis and subsequently overlapped with hub genes differentially expressed across cancer grades. The common targets were mapped to lung cancer associated signaling pathways, revealing EGFR as a highly modulated node. Among the identified metabolites, neoschaftoside emerged as the top-ranked bioactive interacting with EGFR-related hub genes. Later, Molecular docking and molecular dynamics (MD) simulations demonstrated strong binding affinity and conformational stability of the EGFR neoschaftoside complex. Post-MD analyses, including principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) analysis, further indicated restricted global motions and enhanced correlated dynamics, confirming structural stabilization upon ligand binding. Collectively, these findings suggest that neoschaftoside may function as a promising lead compound capable of inhibiting EGFR activity through modulation of EGFR signaling, thereby suppressing oncogenic progression.
Insights
Ailanthus altissima extract contains neoschaftoside, a compound that may inhibit cancer growth by targeting the epidermal growth factor receptor (EGFR) signaling pathway. This discovery offers a potential new avenue for anticancer drug development.
Area of Science:
- Molecular Biology
- Pharmacology
- Computational Chemistry
Background:
- Epidermal growth factor receptor (EGFR) signaling is crucial in cancer proliferation, angiogenesis, and apoptosis resistance.
- Aberrant EGFR activation drives tumor progression and therapeutic resistance, making it a key anticancer target.
- Ailanthus altissima (A. altissima) exhibits anticancer properties, but its mechanisms remain unclear.
Purpose of the Study:
- To identify bioactive constituents from A. altissima that modulate cancer-related proteins.
- To investigate the potential of these constituents to target EGFR signaling in cancer.
- To evaluate the molecular interactions and stability of identified compounds with EGFR.
Main Methods:
- Bioactive constituents of A. altissima were analyzed for protein modulation and overlapped with cancer hub genes.
- Targeted signaling pathways, particularly lung cancer pathways, were mapped.
- Molecular docking and molecular dynamics (MD) simulations were employed to assess ligand-target interactions and complex stability.
Main Results:
- EGFR was identified as a highly modulated node in lung cancer signaling pathways targeted by A. altissima constituents.
- Neoschaftoside was identified as a top bioactive compound interacting with EGFR-related hub genes.
- Molecular docking and MD simulations confirmed strong binding affinity and conformational stability of the neoschaftoside-EGFR complex.
Conclusions:
- Neoschaftoside demonstrates potential as a lead compound for inhibiting EGFR activity.
- Modulation of EGFR signaling by neoschaftoside may suppress oncogenic progression.
- These findings suggest a novel therapeutic strategy targeting EGFR in cancer treatment.
