title: Structural basis of acetylcholinesterase inhibition by triterpenoidal alkaloids.
abstract: Acetylcholinesterase plays a crucial role in the metabolism of neurotransmitter, acetylcholine. Inhibition of Torpedo californica acetylcholinesterase by triterpenoidal alkaloids buxamine-B (1) and buxamine-C (2) has been studied by enzyme kinetics and molecular docking experiments. Buxamine-C (2) has been found to be 20-fold potent than buxamine-B (1) (Ki = 5.5 and 110 microM, respectively). The ligand docking experiments predicted that the cyclopentanophenanthrene skeleton of both inhibitors properly fits into the aromatic gorge of the enzyme. The C-3 and C-20 amino groups of both alkaloids mimic the well-known bis-quaternary ammonium inhibitors such as decamethonium and interact with Trp84 and Trp279 residues of the enzyme, respectively. The C-3 amino group in buxamine-C (2) appears to be better positioned at the bottom of the aromatic gorge and thus seems to be crucial for the inhibitory activity of such inhibitors.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Pakistan.
authors.forename: Asaad
authors.initials: A
authors.lastname: Khalid
authors.forename: M Kamran
authors.initials: MK
authors.lastname: Azim
authors.forename: Shehnaz
authors.initials: S
authors.lastname: Parveen
authors.lastname: Atta-ur-Rahman
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D014101:Torpedo; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D014315:Triterpenes; D000110:Acetylcholinesterase