Simulated Docking of alpha-Conotoxin Interactions with Nicotinic Acetylcholine Receptors

Abstract

The nicotinic acetylcholine receptors (nAChRs) are linked to several biological processes and neurological conditions. The α-conotoxins represent an essential resource for ligands with which to explore structure-function correlations for a variety of nAChR subtypes. With the multitude of nAChR subtypes occurring in vivo, it is imperative to search for subtype-selective ligands to effectively utilize their modulatory functions for their target receptors. In this work,docking simulations using PatchDock showed that either the replacement of Ala10 with the more hydrophobic Leu in PnIA to PnIA[A10L] or the presence of a sulfated tyrosine in the structural scaffold of PnIA[Y15Y] or PnIB[Y15Y] (Y stands for sulfated tyrosine) is sufficient to alter the interactions of α-conotoxins PnIA and PnIB for their target nAChR receptor subtypes – α7and α3β2. The employed protocol can be utilized to screen for ligand docking and amino acid residue interactions of α-conotoxins to certain nAChR subtypes. This was tested on α-conotoxinLoIA, which was predicted to preferentially bind to the α3β2 nAChR over α7 nAChR. The present work is supportive of the idea that the conserved α-conotoxin structural scaffold can be further investigated to guide the synthesis of novel nAChR ligands with greater specificity.The results of this study will be useful in the rational design of selective nAChR antagonists for potential peptide therapeutics.