Exploring the selectivity profile of sigma receptor ligands by molecular docking and pharmacophore analyses.

BACKGROUND Sigma receptors (σRs), initially classified as an additional class of opioid receptors, are now recognized as a unique entity with no homology to opioid receptors divided into two distinct subtypes namely σ1R and σ2R. 1Rtargeting ligands have been conceived and explored for the treatment of various neurodegenerative disorders and neuropathic pain. Activation of the σ2R appears to be involved in the regulation of cellular proliferation and cell death. OBJECTIVE Up to now, the rational design of novel σ1R ligands was efficiently guided by computational methods, especially relying on homology modeling studies. Conversely, the limited number of in silico studies was applied in the search of σ2Rtargeting compounds. Herein we explored by computational methods several series of 1R ligands featuring variable selectivity profile towards σ1R and σR in order to gain useful information guiding the rational design of more selective ligands. METHODS Based on the recent X-ray crystallographic structure of the human σ1R, deepening molecular docking studies on different series of σR ligands have been performed. These calculations have been followed by molecular dynamic simulations (MD) and by two pharmacophore analyses, taking into account the activity levels towards σ1R and σR. RESULTS Structure-based studies revealed key contacts to be achieved in order to guide selectivity of σ1R-targeting compounds while the two pharmacophore models described the main features turning in effective σ1R or σ2R ligands. CONCLUSION The applied computational approach allowed a more comprehensive exploration of the structure-activity relationship (SAR) within the herein analyzed R ligands, deriving useful guidelines for the rational design of more selective compo.