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A Comprehensive Ligand Based Mapping of the σ2 Receptor Binding Pocket

[ Vol. 10 , Issue. 1 ]

Author(s):

Derek J. Rhoades, David H. Kinder and Tarek M. Mahfouz   Pages 98 - 121 ( 24 )

Abstract:


The sigma (σ ) receptor system consists of at least two major receptor subtypes: σ1 and σ 2. Several potential therapeutic applications would benefit from structural knowledge of the σ 2 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 σ 2 ligands to develop several pharmacophore models for different families of σ 2 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 σ 2 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.

Affiliation:

Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810, USA.



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