Targeting SERPINE1 with Esculetin for Migraine Management: Computational Insights and in-vitro Validation
Abstract
Migraine is a multifactorial neurovascular disorder involving aberrant neuronal excitability, vascular dysregulation, and neuroinflammation. Current therapies often provide incomplete relief and may cause adverse effects, highlighting the need for safer, multi-target interventions. This study explored the potential anti-migraine mechanisms of esculetin, a naturally occurring coumarin derivative with antioxidant, anti-inflammatory, and vasomodulatory properties. Network pharmacology identified SERPINE1 (serpin family E member 1), GSK3B (glycogen synthase kinase 3 beta), STAT1 (signal transducer and activator of transcription 1), IRAK1 (interleukin-1 receptor-associated kinase 1), and CA12 (carbonic anhydrase 12) as hub targets linked to Toll-like receptor signaling, neuroinflammatory regulation, and vascular remodeling. Molecular docking ranked SERPINE1 (plasminogen activator inhibitor-1, PAI-1; PDB: 4AQH) as the highest-affinity target (−7.50 kcal/mol) via dual hydrogen bonds and π–π stacking, followed by GSK3B and STAT1. Molecular dynamics (MD) simulations confirmed stable esculetin–SERPINE1 binding with consistent root-mean-square deviation (RMSD) and persistent hydrogen bond occupancy, indicating sustained interaction under physiological conditions. In vitro assays using U-87 glioblastoma cells showed preserved viability (>85%) at 6.25–50 μM, while higher concentrations induced dose-dependent cytotoxicity (half-maximal inhibitory concentration, IC₅₀ ≈ 220 μM).…
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