title: Modeling binding modes of alpha7 nicotinic acetylcholine receptor with ligands: the roles of Gln117 and other residues of the receptor in agonist binding.
abstract: Extensive molecular docking, molecular dynamics simulations, and binding free energy calculations have been performed to understand how alpha7-specific agonists of nicotinic acetylcholine receptor (nAChR), including AR-R17779 (1), GTS-21 (4), and 4-OH-GTS-21 (5), interact with the alpha7 receptor, leading to important new insights into the receptor-agonist binding. In particular, the cationic head of 4 and 5 has favorable hydrogen bonding and cation-pi interactions with residue Trp149. The computational results have also led us to better understand the roles of Gln117 and other residues in the receptor binding with agonists. The computational predictions are supported by data obtained from wet experimental tests. The new insights into the binding and structure-activity relationship obtained from this study should be valuable for future rational design of more potent and selective agonists of the alpha7 receptor.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Huang
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Clare
authors.initials: C
authors.lastname: Stokes
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D003198:Computer Simulation; D005973:Glutamine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D005973:Glutamine