Artículos de revistas
In silico characterization of cytisinoids docked into an acetylcholine binding protein
Fecha
2010-05-06Registro en:
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume: 20, Issue: 12, Pages: 3683-3687, 2010
0960-894X
Autor
Abin Carriquiry, Juan Andrés
Paulino Zunini, Margot
Cassels Niven, Bruce
Wonnacott, Susan
Dajas, Federico
Institución
Resumen
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.