title: Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning.
abstract: Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus.
authors.affiliation: Oak Ridge National Laboratory, Oak Ridge, Tennessee.
authors.forename: Andrey
authors.initials: A
authors.lastname: Kovalevsky
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Blumenthal
authors.affiliation: Oak Ridge National Laboratory, Oak Ridge, Tennessee.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California.
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California. zradic@ucsd.edu.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000201:enzymology; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D000110:Acetylcholinesterase
keywords: X-ray structure; acetylcholinesterase; nucleophilic reactivation; organophosphate; oxime antidote; protein backbone flexibility