In silico characterization of cytisinoids docked into an acetylcholine binding protein |
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Authors: | Juan Andrés Abin-Carriquiry Margot Paulino Zunini Bruce K. Cassels Susan Wonnacott Federico Dajas |
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Affiliation: | 1. Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, Montevideo, Uruguay;2. LaBioFarMol, DETEMA, Facultad de Química, Universidad de la República, Montevideo, Uruguay;3. Departamentos de Física y Química y Farmacia, Facultad de Ciencias, Universidad Católica del Norte, Antofagasta, Chile;4. Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile;5. Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK |
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Abstract: | 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 α4β21 nAChRs over the homomeric α7 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 α4β21 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 α4β21/α7 selectivity. |
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