Resveratrol as a Dual Inhibitor of BRAFV600E and STAT3: Molecular Docking Insights for Glioblastoma Therapy

Background: Glioblastoma (GBM) remains the most aggressive primary brain malignancy with limited therapeutic options. Although dabrafenib demonstrates clinical efficacy against BRAFV600E mutations, sustained responses are compromised by adaptive resistance, particularly through STAT3 pathway activation. While resveratrol (RES) exhibits suppressive effects on mitogen-activated protein kinase and STAT3 signaling in GBM models, direct molecular interactions with BRAFV600E and STAT3 remain uncharacterized. This study investigates these binding interactions through molecular docking analysis. Methods: Molecular docking was performed using AutoDock Vina to evaluate binding interactions of dabrafenib and RES with BRAFV600E (Protein Data Bank [PDB]: 4XV2), and RES with STAT3 (PDB: 6NJS). Protein and ligand structures underwent standard optimization, followed by systematic analysis of binding affinities, interaction profiles, and conformational stability. Results: Dabrafenib exhibited superior binding affinity to BRAFV600E (−10.0 kcal/mol) compared to RES (−8.2 kcal/mol). RES demonstrated dual-targeting capability with moderate affinity toward BRAFV600E (−8.2 kcal/mol) and STAT3 (−5.8 kcal/mol). Interaction analysis revealed that dabrafenib forms extensive hydrogen bonds and halogen interactions with BRAFV600E, whereas RES engages through hydrogen bonding, pi-sulfur, and pi-sigma interactions with BRAFV600E, and hydrogen bonds with pi–pi interactions at STAT3. Conclusion: This computational study provides molecular evidence supporting RES as a dual inhibitor targeting BRAFV600E and STAT3, addressing resistance pathways in GBM. While dabrafenib remains superior for BRAFV600E inhibition, RES multitarget profile suggests potential as adjuvant therapy. These findings warrant experimental validation and investigation into combination therapeutic strategies.