Ligand docking in the sigma-1 receptor compared to the sigma-1 receptor-BiP complex and the effects of agonists and antagonists on C. elegans lifespans.

Model organisms are commonly used to study human diseases; we set out to understand the relevance of several model organisms with relation to the σ1R protein. The study explored the interactions of σ1R with various agonists, antagonists across different species. Ligand and protein-protein (σ1R-BiP) docking approaches were used to understand the significance of σ1R in modulating neuroprotective mechanisms and its potential role in Alzheimer's. Ligand docking revealed that common σ1R antagonists generally exhibited stronger σ1R binding than commonly used agonists. Human σ1R showed high binding affinity for S1RA and NE100. Orthologs in yeast, slime mold, and C. elegans displayed varied binding affinities, indicating evolutionary adaptation in their binding pockets. We evaluated the relevance of σ1R-ligand interactions in C. elegans, measuring life-spans showing the impact of ligands on lifespan depends on genetic background and amyloid-beta pathology. Haloperidol (5-10 mM) extended wild-type worms' lifespan, but this effect was absent in the σ1R-KO, suggesting at least a partial role for the σ1R. Fluoxetine (5-10 mM) also promoted a small increase in longevity in wild-type worms but was not seen in the σ1R-KO strain. BD1047 (5 & 10 mM) reduced the lifespan of amyloid-beta-expressing transgenic worms, whereas dipentylamine (DPA) (5 mM) significantly increased the lifespan in a σ1R antagonist-sensitive manner. These findings highlight the importance of the σ1R in neurodegeneration and suggest that ligand interactions are modulated by BiP. Further research using in-vitro and in-vivo models is needed to clarify σ1R's therapeutic potential in neurodegenerative diseases, where modulating σ1R could provide neuroprotective effects.