title: QM-polarized ligand docking accurately predicts the trend in binding affinity of a series of arylmethylene quinuclidine-like derivatives at the α4β2 and α3β4 nicotinic acetylcholine receptors (nAChRs).
abstract: Compounds containing a quinuclidine scaffold are promising drug candidates for pharmacological management of the central nervous system (CNS) pathologies implicating nAChRs. We have carried out binding affinity and in-silico docking studies of arylmethylene quinuclidine-like derivatives at the α4β2 receptor using in-vitro receptor binding assay and comparative modeling, respectively. We found that introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative resulted in a 266-fold increase in binding affinity and confers agonism properties. By contrast, addition of a phenyl group to 3-benzylidene quinuclidine derivative only results in an 18-fold increase in binding affinity, without conferring agonism. We also found that docking into the orthosteric binding site of the α4β2 nAChR is consistent with the fact that the basic nitrogen atom donates a hydrogen-bond to the carbonyl group of the highly conserved Trp-149, as initially observed by Dougherty and co-workers.(1) The experimentally-observed trend in binding affinity at both α4β2 and α3β4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3β4 subtype primarily results from a dampening of both coulombic and cation-π interactions.
authors.affiliation: Targacept, Inc, 100 North Main Street, Suite 1510, Winston-Salem, NC 27101-4072, United States. david.kombo@blueatom.us.com
authors.forename: David C
authors.initials: DC
authors.lastname: Kombo
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Grinevich
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Serguei
authors.initials: S
authors.lastname: Sidach
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
mesh_terms: D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011812:Quinuclidines / Q000737:chemistry* / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2
keywords: ACHBP; Ach; Agonism; Arylmethylene quinuclidine-like derivatives; Binding; CNS; EF; Homology modeling; MEC; NIC; Nicotinic acetylcholine receptor; Pdb; QM; QM-polarized docking; QPLD; ROC; SP; XP; acetylcholine; acetylcholine-binding protein; central nervous system; enrichment factor; extra precision; minimum-effective concentration; nAChR; nicotine; nicotinic acetylcholine receptor; protein databank; quantum mechanics polarized ligand docking; quantum-mechanics; receiver operating characteristic curve; rmsd; root-mean-squared-deviation; standard precision