In silico characterization of cytisinoids docked into an acetylcholine binding protein

Reference:

Abin-Carriquiry, J. A., Zunini, M. P., Cassels, B. K., Wonnacott, S. and Dajas, F., 2010. In silico characterization of cytisinoids docked into an acetylcholine binding protein. Bioorganic & Medicinal Chemistry Letters, 20 (12), pp. 3683-3687.

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Official URL:

http://dx.doi.org/10.1016/j.bmcl.2010.04.092

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 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.

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