In Silico Finding of Key Interaction Mediated ?3?4 and ?7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype.

ABSTRACT: The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes ?3?4 and ?7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary ?4-subunit of the ?3?4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the ?3?4 selectivity of the quinuclidine-triazole chemotype, explaining the 47-327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the ?7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

SUBMITTER: Arunrungvichian K 

PROVIDER: S-EPMC7504379 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature