QM-polarized ligand docking accurately predicts the trend in binding affinity of a series of arylmethylene quinuclidine-like derivatives at the α4ß2 and α3ß4 nicotinic acetylcholine receptors (nAChRs).
Bioorg Med Chem Lett
; 23(17): 4842-7, 2013 Sep 01.
Article
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| MEDLINE
| ID: mdl-23886687
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 α4ß2 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 α4ß2 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 α4ß2 and α3ß4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3ß4 subtype primarily results from a dampening of both coulombic and cation-π interactions.
Palabras clave
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
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinuclidinas
/
Receptores Nicotínicos
/
Agonistas Nicotínicos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos