Targeting CXCR4 and TRPV1 with α-Conopeptide G1 derived from Conus for Glioblastoma: an integrative in-silico and network pharmacology approach

Glioblastoma (GBM) was identified as a highly aggressive and lethal primary brain tumor of the central nervous system, marked by significant inter- and intra-tumoral heterogeneity that limited therapeutic efficacy. This study aimed to target glioblastoma stem cells (GSCs) using α-conopeptide GI, employing an in-silico approach to identify and validate therapeutic pathways. Swiss Target Prediction identified 100 potential target genes, and toxicity analysis of α-conopeptide GI demonstrated minimal toxicity. Structural validation using a ramachandran plot confirmed the peptide’s stability, referencing the PDB code 1NOT. Further pathway analyses narrowed the focus to 50 common hub genes using DisGeNET and Venn diagram analysis. STRING network analysis for Protein-Protein Interaction (PPI) interaction conducted using Cytoscape, highlighted key genes with high degree values, including C-X-C chemokine receptor type 4 (CXCR4-score: 31) and transient receptor potential vanilloid 1 (TRPV1-score: 29). Functional annotation through Kyoto encyclopedia of genes and genomes pathway and Gene Ontology analysis linked these genes to critical pathways in cancer, angiogenesis, and IL-17 signaling. Molecular docking studies using ClusPro and Schrödinger software demonstrated strong binding affinities of α-conopeptide GI with CXCR4 (ΔG: −10.7 kcal/mol) and TRPV1 (ΔG: −9.3 kcal/mol). Molecular dynamics simulations further validated these interactions, with Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and ligand torsion profiles falling within optimal ranges (1–3Å). These findings suggested that α-conopeptide GI, derived from Conus geographus, held promise as a therapeutic agent for GBM by targeting tumor recurrence and angiogenesis. Further in-vitro and in-vivo studies are required to confirm its clinical potential.