The sigma (σ) receptor system consists of at least two major receptor subtypes: σ1 and σ2. Several potential
therapeutic applications would benefit from structural knowledge of the σ2 receptor but gaining this knowledge has been
hampered by the difficulties associated with its isolation and, thus, characterization. Here, a ligand based approach has
been adopted using the program PHASE® and a group of 41 potent and structurally diverse σ2 ligands to develop several
pharmacophore models for different families of σ2 ligands. These pharmacophores were analyzed to identify the different
binding modes to the receptor and were combined together to construct a comprehensive pharmacophore that was used to
develop a structural model for the σ2 binding pocket. A total of six binding modes were identified and could be classified
as neutral or charged modes. The results presented here also indicate the significance of hydrophobic interactions to σ2
binding and the requirement of hydrogen bonding interactions to increase the affinity for this receptor subtype. This work
adds breadth to our knowledge of this receptor’s binding site, and should contribute significantly to the development of
novel selective σ2 ligands.
Keywords: Sigma receptor, pharmacophore, 3D QSAR, sigma receptor structural model.
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