title: Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the α7 nicotinic acetylcholine receptor.
abstract: Potentiation of the function of the α7 nicotinic acetylcholine receptor (α7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of α7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed α7-AChBP) constructed from the extracellular domain of α7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of α7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol-1) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with α7-nAChR and is helpful for the development of novel PAMs.
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, S-106 91, Stockholm, Sweden. yaoquan@kth.se.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Kuang
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, S-106 91, Stockholm, Sweden. yaoquan@kth.se.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, 171 76, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center of Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska University Hospital, Huddinge, S-141 86, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.affiliation: Department of Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, S-106 91, Stockholm, Sweden. yaoquan@kth.se.
authors.forename: Hans
authors.initials: H
authors.lastname: Ågren
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, S-106 91, Stockholm, Sweden. yaoquan@kth.se.
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Tu
mesh_terms: D000495:Allosteric Site; D000818:Animals; D006801:Humans; D006860:Hydrogen Bonding; D008195:Lymnaea / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010671:Phenylurea Compounds / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry*
chemical_list: C523981:1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; D010671:Phenylurea Compounds; D011993:Recombinant Fusion Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor