title: Biological Testing of Organophosphorus-Inactivated Acetylcholinesterase Oxime Reactivators Identified via Virtual Screening.
abstract: There is a pressing need for new therapeutics to reactivate covalently inactivated acetylcholinesterase (AChE) due to exposure to organophosphorus (OP) compounds. Current reactivation therapeutics (RTs) are not broad-spectrum and suffer from other liabilities, specifically the inability to cross the blood-brain-barrier. Additionally, the chemical diversity of available therapeutics is small, limiting opportunities for structure-activity relationship (SAR) studies to aid in the design of more effective compounds. In order to find new starting points for the development of oxime-containing therapeutic reactivators and to increase our base of knowledge, we have employed a combination of computational and experimental procedures to identify additional compounds with the real or potential ability to reactivate AChE while augmenting and complementing current knowledge. Computational methods were used to identify previously uninvestigated oxime-containing molecules. Experimentally, six compounds were found with reactivation capabilities comparable to, or exceeding, those of 2-pralidoxime (2-PAM) against a panel of AChE inactivated by paraoxon, diisopropylfluorophosphate (DFP), fenamiphos, and methamidophos. One compound showed enhanced reactivation ability against DFP and fenamiphos, the least tractable of these OPs to be reactivated.
authors: Department of Chemical, Paper and Biomedical Engineering, College of Engineering and Computing, Miami University , 64 P Engineering Building, 650 East High Street, Oxford, Ohio 45056, United States.
authors: Jason A
authors: JA
authors: Berberich
authors: Science For Solutions, LLC , 6211 Kaityln Court, Princeton Junction, New Jersey 08550, United States.
authors: Terry R
authors: TR
authors: Stouch
authors: Center for Computational Sciences, Department of Chemistry & Biochemistry, Duquesne University , 600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.|Department of Chemistry & Biochemistry, Duquesne University , 600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.
authors: Sankar
authors: S
authors: Manepalli
authors: exeResearch, LLC , 32 University Drive, East Lansing, Michigan 48823, United States.
authors: Emilio Xavier
authors: EX
authors: Esposito
authors: Center for Computational Sciences, Department of Chemistry & Biochemistry, Duquesne University , 600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.|Department of Chemistry & Biochemistry, Duquesne University , 600 Forbes Avenue, 308 Mellon Hall, Pittsburgh, Pennsylvania 15282, United States.
authors: Jeffry D
authors: JD
authors: Madura
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D062126:Databases, Chemical; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D009943:Organophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D000110:Acetylcholinesterase