title: Structure-activity approach in the reactivation of tabun-phosphorylated human acetylcholinesterase with bispyridinium para-aldoximes.
abstract: We investigated interactions of bispyridinium para-aldoximes N,N'-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), N,N'-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and N,N'-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings. Shorter linkers than propylene (methylene or ethylene) as in MMB-4 and DMB-4 did not allow appropriate orientation in the active site, and MMB-4 and DMB-4 were not efficient reactivators of tabun-phosphorylated acetylcholinesterase. Since aldoximes are also reversible inhibitors of native acetylcholinesterase, we determined dissociation constants and their protective index against acetylcholinesterase inactivation by tabun.
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia. zkovarik@imi.hr
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Maja
authors.initials: M
authors.lastname: Calić
authors.forename: Goran
authors.initials: G
authors.lastname: Sinko
authors.forename: Anita
authors.initials: A
authors.lastname: Bosak
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002619:Chemical Warfare Agents / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D010755:Organophosphates / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D014289:Trimedoxime / Q000494:pharmacology*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D014289:Trimedoxime; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D000110:Acetylcholinesterase; C009374:tabun