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<p>Glioblastoma (GBM) is one of the most aggressive brain tumors, with poor therapeutic outcomes due to its complex molecular profile. This study investigated the multi-target potential of three natural polyphenols—Ferulic acid, Morin, and Mangiferin—through an integrative computational strategy combining network pharmacology, onco-omics, molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT). Cross-referencing polyphenol-associated targets with GBM-related genes identified 13 common targets (e.g., PTGS2, EGFR, ESR1, MMP9). Protein–protein interaction analysis showed significant connectivity (<i>p</i> = 1.54 × 10⁻<sup>8</sup>), highlighting their relevance in GBM. Gene Ontology and KEGG enrichment revealed roles in proliferation, apoptosis, and migration, with enrichment in PI3K-Akt and MAPK signaling pathways. Molecular docking confirmed stable binding, with Mangiferin showing the strongest affinities: -11.0&#xa0;kcal/mol (6ESM), -8.2&#xa0;kcal/mol (5UGC), -7.5&#xa0;kcal/mol (5UFW), and -9.1&#xa0;kcal/mol (5IKT). MD simulations revealed the 5IKT–Mangiferin complex to be the most stable, with a favorable binding free energy (-32.0 ± 4.4&#xa0;kcal/mol), while PCA and free energy landscapes supported reduced conformational variability. DFT results further supported favorable electronic properties. In vitro assays showed dose-dependent cytotoxicity, with IC<sub>50</sub> values of 9.43&#xa0;µM (Morin), 4.65&#xa0;µM (Mangiferin), and 6.22&#xa0;µM (5-FU). Collectively, Mangiferin emerged as the lead candidate with superior binding stability and multi-target potential against GBM. This integrated framework provides mechanistic insights supporting polyphenol-based therapeutic development and warrants further in vivo validation.</p>

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Polyphenol-based therapeutics for glioblastoma: validation from In-vitro cell viability assay and integrated onco-omics computational analysis

  • 期刊论文

  • 发表日期：

    2025年10月11日

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  • Yogesh H S,
  • Sadik Shaik,
  • Sibghatullah Muhammad Ali Sangi,
  • Krishna Swaroop,
  • Sreeharsha Nagaraja,
  • Anitha K N,
  • Vipin Kumar Mishra,
  • Santosh Prasad Chaudhary Kurmi,
  • Subrata Nath,
  • Shankar Thapa

摘要

Glioblastoma (GBM) is one of the most aggressive brain tumors, with poor therapeutic outcomes due to its complex molecular profile. This study investigated the multi-target potential of three natural polyphenols—Ferulic acid, Morin, and Mangiferin—through an integrative computational strategy combining network pharmacology, onco-omics, molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT). Cross-referencing polyphenol-associated targets with GBM-related genes identified 13 common targets (e.g., PTGS2, EGFR, ESR1, MMP9). Protein–protein interaction analysis showed significant connectivity (p = 1.54 × 10⁻8), highlighting their relevance in GBM. Gene Ontology and KEGG enrichment revealed roles in proliferation, apoptosis, and migration, with enrichment in PI3K-Akt and MAPK signaling pathways. Molecular docking confirmed stable binding, with Mangiferin showing the strongest affinities: -11.0 kcal/mol (6ESM), -8.2 kcal/mol (5UGC), -7.5 kcal/mol (5UFW), and -9.1 kcal/mol (5IKT). MD simulations revealed the 5IKT–Mangiferin complex to be the most stable, with a favorable binding free energy (-32.0 ± 4.4 kcal/mol), while PCA and free energy landscapes supported reduced conformational variability. DFT results further supported favorable electronic properties. In vitro assays showed dose-dependent cytotoxicity, with IC50 values of 9.43 µM (Morin), 4.65 µM (Mangiferin), and 6.22 µM (5-FU). Collectively, Mangiferin emerged as the lead candidate with superior binding stability and multi-target potential against GBM. This integrated framework provides mechanistic insights supporting polyphenol-based therapeutic development and warrants further in vivo validation.