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Bioorg Med Chem Lett. 2013 Sep 15;23(18):5105-13. doi: 10.1016/j.bmcl.2013.07.028. Epub 2013 Jul 23.

Computational studies of novel carbonyl-containing diazabicyclic ligands interacting with α4β2 nicotinic acetylcholine receptor (nAChR) reveal alternative binding modes.

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Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101, USA.


We have carried out computational studies on interactions of diazabicyclic amide analogs with α4β2 nAChR using homology modeling, docking and pharmacophore elucidation techniques. We have found alternative ligand binding modes in most cases. All these diverse poses exhibit the quintessential hydrogen-bonding interaction between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the highly conserved Trp-149. This hydrogen bond was always found to be shorter than the one contracted by the ligand carbonyl group and a second hydrogen-bond made by the cationic center with Tyr-93 of the principal face of the protein. In most of the poses observed, cation-π interactions involved three aromatic residues located in the principal face of the protein: Trp-149, Tyr-190 and Tyr-197. The latter amino acid residue appears to often donate a hydrogen-bond to the ligand carbonyl oxygen atom. We also describe two rings of alternative receptor-based hydrogen-bond donor features equidistantly separated from the carbonyl oxygen of the highly conserved Trp-149 approximately by 5 and 8Å, respectively. These findings could be exploited to design diverse and selective novel chemical libraries for the treatment of diseases and conditions where the α4β2 nAChR is disrupted, such as Alzheimer disease, Parkinson's disease and l-dopa-induced dyskinesia (LID).


ACHBP; Ach; Alternative binding modes; CNS; Docking; Homology modelling; LID; N-Acyl diazabicycle; Nicotinic acetylcholine receptor; Pdb; Pharmacophore elucidation; SAR; SP; XP; acetylcholine; acetylcholine-binding protein; central nervous system; extra precision; l-dopa-induced dyskinesia; nAChR; nicotinic acetylcholine receptor; protein databank; rmsd; root-mean-squared-deviation; standard precision; structure–activity relationship; α4β2 nAChR

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