title: Design of novel alpha7-subtype-preferring nicotinic acetylcholine receptor agonists: application of docking and MM-PBSA computational approaches, synthetic and pharmacological studies.
abstract: In the search for nicotinic acetylcholine receptor (nAChRs) agonists with a selective affinity for the homomeric alpha7 channels, we carried out the virtual screening of a test set of potential nicotinic ligands, and adopted a simplified MM-PBSA approach to estimate their relative binding free energy values. By means of this procedure, previously validated by a training set of compounds, we reached a realistic compromise between computational accuracy and calculation rate, and singled out a small group of novel structurally related derivatives characterized by a promising theoretical affinity for the alpha7 subtype. Among them, five new compounds were synthesized and assayed in binding experiments at neuronal alpha7 as well as alpha4beta2 nAChRs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche 'Pietro Pratesi', Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. giovanni.grazioso@unimi.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Diego Yuri
authors.initials: DY
authors.lastname: Pomè
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.forename: Fabio
authors.initials: F
authors.lastname: Frigerio
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
mesh_terms: D000272:Adipates / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D019295:Computational Biology; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013386:Succinates / Q000378:metabolism*
chemical_list: D000272:Adipates; D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013386:Succinates; C403531:nicotinic receptor alpha4beta2; C437084:poly(tetramethylene succinate-co-tetramethylene adipate)