title: Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo californica acetylcholinesterase using molecular docking.
abstract: The alkaloid (-)-galanthamine is known to produce significant improvement of cognitive performances in patients with the Alzheimer's disease. Its mechanism of action involves competitive and reversible inhibition of acetylcholinesterase (AChE). Herein, we correctly predict the orientation and conformation of the galanthamine molecule in the active site of AChE from Torpedo californica (TcAChE) using a combination of rigid docking and flexible geometry optimization with a molecular mechanics force field. The quality of the predicted model is remarkable, as indicated by the value of the RMS deviation of approximately 0.5A when compared with the crystal structure of the TcAChE-galanthamine complex. A molecular model of the complex between TcAChE and a galanthamine derivative, SPH1107, with a long chain substituent on the nitrogen has been generated as well. The side chain of this ligand is predicted to extend along the enzyme active site gorge from the anionic subsite, at the bottom, to the peripheral anionic site, at the top. The docking procedure described in this paper can be applied to produce models of ligand-receptor complexes for AChE and other macromolecular targets of drug design.
authors.affiliation: Universitaet-GH Paderborn, Chemie und Chemietechnik, Paderborn, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Pilger
authors.forename: C
authors.initials: C
authors.lastname: Bartolucci
authors.forename: D
authors.initials: D
authors.lastname: Lamba
authors.forename: A
authors.initials: A
authors.lastname: Tropsha
authors.forename: G
authors.initials: G
authors.lastname: Fels
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005702:Galantamine / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018697:Nootropic Agents / Q000737:chemistry / Q000627:therapeutic use; D011487:Protein Conformation; D012984:Software; D014101:Torpedo
chemical_list: D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D005702:Galantamine; D000110:Acetylcholinesterase