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

Description

sRs), Background: Sigma receptors ( 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 s1R s2R. subtypes namely and .1R-targeting ligands have been conceived and explored for the s2R treatment of various neurodegenerative disorders and neuropathic pain. Activation of the appears to be involved in the regulation of cellular proliferation and cell death. s1R Objective: Up to now, the rational design of novel ligands was efficiently guided by computational methods, especially relying on homology modeling studies. Conversely, the limited s2R- number of in silico studies was applied in the search of targeting compounds. Herein we explored by computational methods several series of .1R ligands featuring variable selectivity profile towards s1R s and R in order to gain useful information guiding the rational design of more selective ligands. . s1R, Methods: Based on the recent X-ray crystallographic structure of the human deepening sR molecular docking studies on different series of ligands have been performed. These calculations have been followed by molecular dynamic simulations (MD) and by two pharmacophore analyses, s1R s taking into account the activity levels towards and .R. Results: Structure-based studies revealed key contacts to be achieved in order to guide selectivity of s1R -targeting compounds while the two pharmacophore models described the main features turning in s1R s2R effective or 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 compounds.

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