title: Binding of tacrine and 6-chlorotacrine by acetylcholinesterase.
abstract: Multiconfiguration thermodynamic integration was used to determine the relative binding strength of tacrine and 6-chlorotacrine by Torpedo californica acetylcholinesterase. 6-Chlorotacrine appears to be bound stronger by 0.7+/-0.4 kcal/mol than unsubstituted tacrine when the active site triad residue His-440 is deprotonated. This result is in excellent agreement with experimental inhibition data on electric eel acetylcholinesterase. Electrostatic Poisson-Boltzmann calculations confirm that order of binding strength, resulting in deltaG of binding of -2.9 and -3.3 kcal/mol for tacrine and chlorotacrine, respectively, and suggest inhibitor binding does not occur when His-440 is charged. Our results suggest that electron density redistribution upon tacrine chlorination is mainly responsible for the increased attraction potential between pronated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84.
authors.affiliation: Department of Chemistry, University of Houston, TX 77204-5641, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Wlodek
authors.forename: J
authors.initials: J
authors.lastname: Antosiewicz
authors.forename: J A
authors.initials: JA
authors.lastname: McCammon
authors.forename: T P
authors.initials: TP
authors.lastname: Straatsma
authors.forename: M K
authors.initials: MK
authors.lastname: Gilson
authors.forename: J M
authors.initials: JM
authors.lastname: Briggs
authors.forename: C
authors.initials: C
authors.lastname: Humblet
authors.forename: J L
authors.initials: JL
authors.lastname: Sussman
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D013619:Tacrine / Q000031:analogs & derivatives* / Q000378:metabolism*; D013816:Thermodynamics; D014101:Torpedo / Q000378:metabolism
chemical_list: C098212:6-chlorotacrine; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase