In silico characterization of cytisinoids docked into an acetylcholine binding protein

J A Abin-Carriquiry, M P Zunini, B K Cassels, Susan Wonnacott, F Dajas

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20 Citations (SciVal)


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 alpha 4 beta 2* nAChRs over the homomeric alpha 7 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 (R-2 = 0.96) between the experimental pIC(50) values at alpha 4 beta 2* 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 alpha 4 beta 2*/alpha 7 selectivity.
Original languageEnglish
Pages (from-to)3683-3687
Number of pages5
JournalBioorganic & Medicinal Chemistry Letters
Issue number12
Publication statusPublished - 15 Jun 2010


  • docking
  • cytisinoids
  • nicotinic acetylcholine receptors
  • acetylcholine binding protein


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