title: Drug-like leads for steric discrimination between substrate and inhibitors of human acetylcholinesterase.
abstract: Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P-site) near the mouth of the active-site gorge. Compounds that bind to this site may selectively block access to the acylation site (A-site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using AutoDock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A-site or P-site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A-site only and in both and A- and P-sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P-site in an inhibitor competition assay.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wildman
authors.forename: Xiange
authors.initials: X
authors.lastname: Zheng
authors.forename: David
authors.initials: D
authors.lastname: Sept
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Auletta
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.forename: Garland R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000122:Acetylthiocholine / Q000378:metabolism; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D002800:Cholinesterase Inhibitors; D000122:Acetylthiocholine; D000110:Acetylcholinesterase