Network Pharmacology and Molecular Docking Insights into N-Mannich Base of Quinazolin-4(3H)-one Derivatives as Potential Multi-Target Agents against Glioblastoma and Inflammation

Author

Mrs. Tamilarasi G, Hameedhash R, Archana A, Ajin TS, Priya M, Srimathi D


Abstract

 Introduction: Glioblastoma (GBM) is the most aggressive primary brain tumor, and its growth is sustained by chronic inflammation and redundant signaling through EGFR, VEGFR and JAK-STAT pathways, which is why single-target therapy often fails. N-Mannich bases of quinazolin-4(3H)-one are attractive scaffolds for multi-target design. This study evaluated six such derivatives (3A–3F) as potential multi-target agents against glioblastoma and inflammation using computational methods.

Materials and Methods: Structures were drawn in ChemSketch and ChemDraw, and their physicochemical, ADME and toxicity profiles were predicted with SwissADME, pkCSM and ProTox-II. Targets were predicted with SwissTargetPrediction and overlapped with glioblastoma and inflammation genes from GeneCards. A protein–protein interaction network was built in STRING and analyzed in Cytoscape, and KEGG and GO enrichment were done with ShinyGO. Docking was performed in PyRx against EGFR (1M17), VEGFR (4ASD) and JAK1 (5E1E) and compared with gefitinib, sorafenib and upadacitinib.

Results and Discussion: All six compounds satisfied Lipinski’s rule of five. ProTox-II predicted no hepatotoxicity, carcinogenicity, mutagenicity or cytotoxicity, with predicted LD₅₀ values of 255–2000 mg/kg. A total of 126 targets were shared between the compounds, glioblastoma and inflammation. The network had 51 nodes and 100 edges (PPI enrichment P < 1.0e–16), with EGFR, JAK2 and ERBB2 as the top hub genes, and KEGG enrichment highlighted EGFR tyrosine kinase inhibitor resistance, JAK-STAT and PI3K-Akt signaling. Docking energies ranged from −7.3 to −8.3 kcal/mol (EGFR), −8.4 to −9.7 kcal/mol (VEGFR) and −7.7 to −9.0 kcal/mol (JAK1). Compound 3E scored best against all three targets (−8.3, −9.7 and −9.0 kcal/mol), stronger than gefitinib for EGFR and equal to upadacitinib for JAK1, but weaker than sorafenib for VEGFR.

Conclusion: Compound 3E was the most promising derivative, showing the strongest predicted binding to EGFR, VEGFR and JAK1 together with a favorable drug-likeness and safety profile. These results are computational only and need experimental validation.



Keywords

Glioblastoma; Quinazolin-4(3H)-one; N-Mannich base; Network pharmacology; Molecular docking; EGFR; JAK1.



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