Introduction: Migraine, one of the most prevalent disabling neurological disorders, is characterized by recurrent severe headache attacks accompanied by photophobia, nausea, and vomiting, imposing a substantial burden on patients’ quality of life and society. Its global prevalence (approximately 15% of the population) and impact on daily productivity underscore the urgent need for effective, cost-efficient therapeutic strategies. At the molecular level, calcitonin gene-related peptide (CGRP)—a potent vasodilatory neuropeptide—plays a central role in migraine pathophysiology. Elevated CGRP levels during migraine attacks and the induction of headaches in susceptible individuals after its administration have established it as a key target for therapeutic interventions.
Novel pharmacological approaches, such as CGRP inhibitors (e.g., ubrogepant) and monoclonal antibodies (e.g., erenumab), have shown remarkable efficacy in reducing attack frequency and severity. However, high costs, limited accessibility, and potential side effects (e.g., nausea, fatigue, immunological reactions) restrict their widespread use. These challenges necessitate the search for natural, safe, and affordable alternatives. Grape seed extract (GSE), rich in polyphenols—including proanthocyanidin, gallic acid, quercetin, and rutin—has emerged as a promising candidate due to its antioxidant and anti-inflammatory properties. Proanthocyanidin, the primary component of GSE, has attracted attention for its neuroprotective and anti-neuroinflammatory effects. Preliminary studies suggest GSE’s potential to modulate migraine-associated inflammatory pathways, including CGRP downregulation. Against this backdrop, this study aims to investigate the inhibitory potential of proanthocyanidin and other GSE constituents against CGRP via molecular docking, providing a foundation for developing natural adjuvant therapies in migraine management.
Methods: To investigate molecular interactions between calcitonin gene-related peptide (CGRP) and bioactive compounds in grape seed extract (GSE), structural data were sourced from validated repositories. The 3D structure of CGRP was retrieved from the Protein Data Bank (PDB), the primary repository for experimentally determined atomic-resolution protein structures. Selection of PDB ensured access to high-fidelity crystallographic data essential for molecular docking simulations. Supplementary sequence and biochemical data for CGRP were obtained from UniProt to confirm alignment with the selected structure.
Following data collection, structure preparation—a critical pre-docking step—was performed. The raw CGRP structure (downloaded from PDB) often contained non-relevant elements (e.g., unrelated protein chains, water molecules, ions, or bound ligands) that could introduce noise or bias into docking results. Thus, UCSF Chimera was used to refine the structure: non-functional protein chains were removed to prevent interference with binding site identification, and extraneous ions/water molecules were deleted to simplify the model. Hydrogen atoms were added (where needed), and the structure’s energy was minimized to ensure stability in simulation environments. This process ensured CGRP was prepared in a biologically relevant state, free of confounding factors.
Similarly, 3D structures of GSE bioactives (e.g., proanthocyanidin, gallic acid, quercetin, rutin) were extracted from PubChem, a trusted database for small-molecule chemical and structural data. These structures were also processed in Chimera to correct structural errors (e.g., missing atoms, incorrect bonds) and optimize geometry/charge distribution—key for realistic interaction simulations with CGRP.
Results: Molecular docking simulations using PyRx 0.8 and AutoDock Vina evaluated interactions between CGRP and GSE bioactives. Key outcomes include:
Proanthocyanidin exhibited the strongest binding affinity (-13.8 kcal/mol) with near-perfect structural stability (RMSD = 0 Å), outperforming even the clinical CGRP inhibitor Ubrogapant (-9 to -10 kcal/mol).
Gallic acid and rutin showed strong/moderate binding (-8.6 and -8.2 kcal/mol) with acceptable stability (RMSD < 6 Å).
Quercetin displayed weaker interactions (-7.1 kcal/mol) and higher instability (RMSD > 27 Å).
These results position proanthocyanidin as a leading candidate for natural CGRP inhibition, comparable to synthetic drugs.
Conclusion: The molecular docking study demonstrates that proanthocyanidin, a key component of grape seed extract (GSE), exhibits exceptional binding affinity to calcitonin gene-related peptide (CGRP), outperforming both the synthetic CGRP inhibitor ubrogepant and other GSE polyphenols (gallic acid, quercetin, rutin). This positions proanthocyanidin as a leading candidate for natural CGRP inhibition.
However, further laboratory and human clinical trials are essential to validate these findings, determine therapeutic efficacy, optimal dosing, and long-term safety before clinical application.
Despite this, the study suggests GSE holds promise as a complementary therapy for migraine management. Proanthocyanidin’s strong CGRP binding, combined with GSE’s inherent antioxidant and anti-inflammatory properties, supports its potential to alleviate migraine symptoms. The superiority of proanthocyanidin over ubrogepant underscores the value of natural compounds in migraine treatment and highlights the need for expanded research in this area.