title: In silico characterization of cytisinoids docked into an acetylcholine binding protein.
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 alpha4beta2* nAChRs over the homomeric alpha7 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 alpha4beta2* 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 alpha4beta2*/alpha7 selectivity.
authors.affiliation: Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. abin@adinet.com.uy
authors.forename: Juan Andrés
authors.initials: JA
authors.lastname: Abin-Carriquiry
authors.forename: Margot Paulino
authors.initials: MP
authors.lastname: Zunini
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
authors.forename: Susan
authors.initials: S
authors.lastname: Wonnacott
authors.forename: Federico
authors.initials: F
authors.lastname: Dajas
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000818:Animals; D001392:Azocines / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D003460:Crystallization; D008195:Lymnaea; D015394:Molecular Structure; D009538:Nicotine / Q000737:chemistry*; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry; D011807:Quinolizines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D014961:X-Ray Diffraction; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D002352:Carrier Proteins; D009538:Nicotine; D011728:Pyridones; D011807:Quinolizines; D011978:Receptors, Nicotinic; C428944:AChBP protein, Lymnaea; C403531:nicotinic receptor alpha4beta2; C004712:cytisine; D000093843:Quinolizidine Alkaloids