A new nicotinic acetylcholine minireceptor model: a theoretical thermodynamic analysis of simultaneous cation-pi and hydrogen bond interactions

In this work, we developed a nicotinic acetylcholine receptor (nAChR) model using the minireceptor modeling technique. For the construction of the minireceptor model, we elected some known nicot inic agonists according to their structural characteristics and binding con stants (Ki) values, The results show an orientation pattern for the probes' distances and angles in the model, These data suggest that the strategy us ed to build the minireceptor is able to reproduce geometrically the cation- pi and hydrogen bond interactions between ligands and the nAChR, In order to obtain an energetic validation for the minireceptor, we derived a quantitative model of interaction that includes the desolvation step of the ligands for all ligand-minireceptor complexes. We observed a good agree ment between the experimental and the calculated free-energy of complexatio n. This new nAChR minireceptor model can be employed in the molecular design o f new nicotinic agonist candidates that may represent new lead-compounds fo r the treatment of cognitive disorders. (C) 2000 Elsevier Science B.V. All rights reserved.