title: Docking to flexible nicotinic acetylcholine receptors: a validation study using the acetylcholine binding protein.
abstract: Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural surrogate and homology modeling template for the nAChRs, the conformation of this loop is controlled by the ligand present in the binding pocket. As part of the development of a protocol for unbiased docking to the nAChRs, we here present the results of docking of ligands with known binding modes to an AChBP ensemble with systematic variations in C-loop closure generated via a series of targeted geometry optimizations. We demonstrate the ability to correctly predict binding modes for 12 out of 15 ligands and induced degrees of C-loop closure for 14 out of 15 ligands. Our approach holds a promising potential for structure based drug discovery within nAChRs and related receptors.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Tommy
authors.initials: T
authors.lastname: Sander
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bruun
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D008024:Ligands; D011978:Receptors, Nicotinic