Targeting CXCR4 and TRPV1 with α-Conopeptide G1 derived from Conus for Glioblastoma: an integrative in-silico and
Sandhanam Kuppusamy1, Sumithra Mohan1
1Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu 603203 Tamil Nadu, India.
Abstract:
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.
Insights
This study explored α-conopeptide GI as a novel glioblastoma (GBM) therapy. Computational analysis identified CXCR4 and TRPV1 as key targets, showing potential for treating this aggressive brain cancer.
Area of Science:
- Computational biology
- Drug discovery
- Neuro-oncology
Background:
- Glioblastoma (GBM) is a lethal brain tumor with high heterogeneity limiting treatment.
- Glioblastoma stem cells (GSCs) are crucial for tumor recurrence and therapeutic resistance.
Purpose of the Study:
- To investigate α-conopeptide GI as a potential therapeutic agent against GBM.
- To identify and validate therapeutic targets and pathways for GBM using in-silico methods.
Main Methods:
- Utilized Swiss Target Prediction, DisGeNET, Venn diagrams, and STRING for pathway and gene analysis.
- Performed structural validation (Ramachandran plot), molecular docking (ClusPro, Schrödinger), and molecular dynamics simulations.
- Analyzed protein-protein interaction networks using Cytoscape to identify key genes like CXCR4 and TRPV1.
Main Results:
- α-conopeptide GI showed minimal toxicity and high stability.
- Identified CXCR4 and TRPV1 as significant targets with strong binding affinities to α-conopeptide GI.
- Pathway analysis linked identified genes to cancer, angiogenesis, and IL-17 signaling pathways.
Conclusions:
- α-conopeptide GI shows promise as a therapeutic agent for glioblastoma by targeting GSCs, recurrence, and angiogenesis.
- Further in-vitro and in-vivo studies are warranted to confirm the clinical efficacy of α-conopeptide GI for GBM treatment.
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