In silico characterization of cytisinoids docked into an acetylcholine binding protein
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Homology models of nicotinic acetylcholine receptors (nAChRs) suggest that subtype specificity is due to non-conserved residues in the complementary subunit of the ligand-binding pocket. Cytisine and its derivatives generally show a strong preference for heteromeric a4b2* nAChRs over the homomeric a7 subtype, and the structural modifications studied do not cause large changes in their nAChR subtype selectivity. In the present work we docked cytisine, N-methylcytisine, and several pyridone ring-substituted cytisinoids into the crystallographic structure of the Lymnaea stagnalis acetylcholine binding protein (AChBP) co-crystallized with nicotine (1UW6). The graphical analysis of the best poses showed that cytisinoids have weak interactions with the side chains of the non-conserved amino acids in the complementary subunit justifying the use of PDB 1UWB as a surrogate for nAChR. Furthermore, we found a high correlation (R2 = 0.96) between the experimental pIC50 values at a4b2* nAChR and docking energy (S) of the best cytisinoid poses within the AChBP. Due to the quality of the correlation we suggest that this equation might be used as a predictive model to propose new cytisine-derived nAChRs ligands. Our docking results also suggest that further structural modifications of these cytisinoids will not greatly alter their a4b2*/a7 selectivity.
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This study was partially supported by Wellcome Trust Collaborative Initiative Grant 073295/Z/03/Z, Programa de Desarrollo de Ciencias Básicas (PEDECIBA) and Agencia Nacional de Investigación e Innovación (ANII) —Fondo Clemente Estable (FCE 2007_421).
Quote ItemBIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume: 20, Issue: 12, Pages: 3683-3687, 2010