I12 Deciphering the neuroprotective role of sigma1 receptor, an important function to overcome the symptoms of neurodegenerative disorders

Background Huntington’s Disease (HD) is a devastating and presently untreatable neurodegenerative disease, characterized by progressively disabling motor and mental manifestations. Sigma-1 receptor (σ1R), whose 3D structure has been recently determined by X-ray crystallography, is expressed in the central nervous system, and σ1R agonists have been shown to possess neuroprotective activity in neurodegenerative diseases. Aims Our overall aim is to exploit σ1R neuroprotective activity for HD therapy. Methods We are integrating computational and experimental methods: i) Virtual Screening (VS) of compound libraries available through the ZINC database towards σ1R; ii) Experimental ligand binding to purified σ1R in vitro by Surface Plasmon Resonance; iii) Assessment of ligand ability to improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells. Additionally, we are performing Molecular Dynamics (MD) simulations to elucidate the mechanism of ligand entrance to σ1R binding site. Results i) Six known drugs have been demonstrated to be able to bind purified σ1R in vitro and improve survival and growth of HD fibroblasts; ii) Several human metabolites have been predicted by VS to bind σ1R. iii) Predictions on routes of ligand entrance have been provided by MD studies. Conclusions Our results support the validity of σ1R as a molecular target for HD therapy, and of the drug repositioning procedure implemented herein for the identification of new therapeutic agents against HD. Experimental validation of metabolites selected by VS and results of MD simulations will contribute to identify endogenous σ1R ligand(s) and mechanism of σ1R entrance.