| الملخص: | The ε-containing GABA (A) receptors (GABAARs), a lesser-studied subtype within the GABAAR family, have gained attention due to their distinct pharmacological properties and potential involvement in brain injury. Zolpidem (ZPM), a widely used Z-drug, has been reported to induce paradoxical effects in brain-injured patients, although the molecular basis remains unclear. This study aimed to elucidate the structural and molecular mechanisms underlying this phenomenon through a comprehensive in silico approach. A homology model of the α1-β2-ε-α1-β2 GABAAR was successfully constructed and validated following energy minimization and equilibration using CHARMM-GUI and GROMACS. Molecular docking with AutoDock 4.2 assessed the binding affinities and interaction profiles of ZPM, flumazenil (FMZ), and methyl-6,7-dimethoxy-4-ethyl-β-carboline-2-carboxylate (DMCM) —representing positive, null, and negative allosteric modulators, respectively. ZPM exhibited the highest binding affinity at the α1+/ε− interface, followed by FMZ and DMCM. Structural analysis suggested that the γ2F77I and γ2A79S substitutions in the ε subunit may reduce ligand affinity, especially for bulkier ligands like FMZ and DMCM. Additionally, poor conservation of Loop F residues spanning γ2Glu182–Arg197 may influence modulatory efficacy of positive allosteric modulators (PAMs) like ZPM. Molecular dynamics simulations (100 ns) largely supported the pharmacological profiles of the ligands. Although ZPM showed limited activity at the α/ε site, the Monod-Wyman-Changeux allosteric model suggests that PAMs can enhance function in spontaneously active GABAARs with single GABA occupancy. This supports ZPM’s specific positive modulatory effects on ε-containing receptors and highlights their potential as therapeutic targets in brain injury.
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