title: Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
abstract: To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Foundation for Medical Education and Research, 200 First Street SW, Rochester, MN 55905, USA. pang@mayo.edu
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kollmeyer
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Jong-Cheol
authors.initials: JC
authors.lastname: Lee
authors.forename: Pamela I
authors.initials: PI
authors.lastname: Hammond
authors.forename: Sharie P
authors.initials: SP
authors.lastname: Haugabouk
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000475:Alkenes / Q000138:chemical synthesis*; D001665:Binding Sites; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis*; D003198:Computer Simulation; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011220:Pralidoxime Compounds / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; D000110:Acetylcholinesterase