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

Jason A Berberich1, Terry R Stouch2, Sankar Manepalli3,4

  • 1Department 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.

Chemical Research in Toxicology
|August 6, 2016
PubMed

Insights

New oxime-containing compounds were identified to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds. These novel therapeutics show promise for treating OP exposure, addressing limitations of current treatments.

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Toxicology

Background:

  • Organophosphorus (OP) compounds irreversibly inhibit acetylcholinesterase (AChE), necessitating novel therapeutic reactivators.
  • Current reactivation therapeutics (RTs) lack broad-spectrum activity, fail to cross the blood-brain-barrier, and have limited chemical diversity for structure-activity relationship (SAR) studies.

Purpose of the Study:

  • To discover new oxime-containing compounds for reactivating AChE inhibited by OP agents.
  • To expand the knowledge base and identify novel starting points for therapeutic development.

Main Methods:

  • Employed a hybrid approach combining computational screening and experimental validation.
  • Computational methods identified novel oxime-containing molecules for investigation.
  • Experimental assays evaluated the efficacy of identified compounds against AChE inhibited by various OP agents.

Main Results:

  • Six compounds demonstrated AChE reactivation capabilities comparable to or better than 2-pralidoxime (2-PAM).
  • Tested compounds were effective against AChE inhibited by paraoxon, diisopropylfluorophosphate (DFP), fenamiphos, and methamidophos.
  • One novel compound exhibited superior reactivation against DFP and fenamiphos, challenging OP agents.

Conclusions:

  • Identified novel oxime-containing compounds as potential therapeutic reactivators for OP-induced AChE inhibition.
  • These findings offer new avenues for developing broader-spectrum and more effective treatments for OP poisoning.
  • The study expands the chemical space for oxime-based AChE reactivators, facilitating future SAR studies.

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