Biological Testing of Organophosphorus-Inactivated Acetylcholinesterase Oxime Reactivators Identified via Virtual Screening.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: Washington, DC : American Chemical Society, c1988-
    • Subject Terms:
      Computer Simulation*; Acetylcholinesterase/*chemistry ; Acetylcholinesterase/*metabolism ; Organophosphorus Compounds/*chemistry ; Oximes/*chemistry; Databases, Chemical ; Enzyme Activation/drug effects ; Erythrocytes/enzymology ; Humans ; Molecular Structure ; Organophosphorus Compounds/pharmacology ; Oximes/pharmacology ; Pralidoxime Compounds/chemistry ; Pralidoxime Compounds/pharmacology ; Structure-Activity Relationship
    • 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.
    • Accession Number:
      0 (Organophosphorus Compounds)
      0 (Oximes)
      0 (Pralidoxime Compounds)
      EC 3.1.1.7 (Acetylcholinesterase)
    • Publication Date:
      Date Created: 20160806 Date Completed: 20170714 Latest Revision: 20180125
    • Publication Date:
      20231215
    • Accession Number:
      10.1021/acs.chemrestox.6b00198
    • Accession Number:
      27494215