aMolecular Insights into Stereoselective Binding of Quinuclidine-Triazole Derivatives to a7 and a3b4 Nicotinic Acetylcholine Receptors

An investigation on the selective binding of six quinuclidine-triazole enantiomeric pairs to nicotinic acetylcholine receptor (nAChR) subtypes, (S)-enantiomers for a3b4-nAChR and its (R)-counterpart for a7-nAChR, was performed in silico to provide the insight into the molecular basis for subtype discrimination of the quinuclidine-triazole enantiomers. The homology modeling and molecular docking analyses revealed that unique amino acid residues in the complementary subunit of nAChR subtypes are related to a high subtype selectivity profile. One non-conserved residue AspB173 in a complementary b4-subunit of the a3b4-nAChR binding pocket was found to be a primary determinant for the a3b4 selectivity of the quinuclidine-triazole chemotype as evidenced by the more pronounced enantioselectivity of (S)-enantiomers for the a3b4 nAChR, 47-326 times greater than its corresponding (R)-enantiomers. For (R)-enantiomers toward the a7 subtype, the interacting amino acid residues were the conserved TyrA93 and TrpA149 and TrpB55, leading to a lesser degree of stereoselectivity. The interaction with non-conserved amino acid residues in the complementary subunit of nAChR subtypes appeared to be the determinant for the nAChR subtype-selective binding, particularly at the heteropentameric subtype.