title: QSAR study of a large set of 3-pyridyl ethers as ligands of the alpha4beta2 nicotinic acetylcholine receptor.
abstract: Extensive 3D-QSAR studies were performed on 158 diverse analogues of 3-pyridyl ethers, which are excellent ligands of alpha4beta2 neuronal nicotinic acetylcholine receptor (NnAChR). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to relate the binding affinities with the ligand structures. Two QSAR models were obtained using CoMFA and CoMSIA techniques. The two QSAR models were proved to be statistically significant and have high predictive power. The best CoMFA model yielded the cross-validated q(2)=0.605 and the non-cross-validated r(2)=0.862. The derived model indicated the importance of steric (85.9%) as well as electrostatic (14.1%) contributions. The CoMFA model demonstrated the steric field as the major descriptor of the ligand binding. The best CoMSIA model gave q(2)=0.723 and r(2)=0.685. This model showed that steric (30.3%) and H-bond interaction (61.8%) properties played major roles in ligand binding process. The squares of correlation coefficient for external test set of 28 molecules were 0.723 and 0.685 for the CoMFA model and the CoMSIA model, respectively. The two models were further graphically interpreted in terms of field contribution maps. SAR studies were also performed on different series of compounds in order to get a more reasonable understanding of the interactions between the ligands and the receptor. With the results, we have also presumed some assistant elements as supplements to the traditional pharmacophoric elements. A crude vision of ligand localization in the ligand-binding pocket of the receptor was also obtained, which would favor for the docking study of this kind of ligands.
authors.affiliation: Department of Chemistry, Beijing Normal University, 19# Street Xinjiekou, Beijing 100875, China. hbzhang@bnu.edu.cn
authors.forename: Huabei
authors.initials: H
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Ma
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D004987:Ethers / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity
chemical_list: D004987:Ethers; D008024:Ligands; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2