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

• Published in: Chemical research in toxicology Vol. 29; no. 9; pp. 1534 - 1540
• Main Authors: Berberich, Jason A, Stouch, Terry R, Manepalli, Sankar, Esposito, Emilio Xavier, Madura, Jeffry D
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.09.2016
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Computer Simulation; Databases, Chemical; Enzyme Activation - drug effects; Erythrocytes - enzymology; Humans; Molecular Structure; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Oximes - chemistry; Oximes - pharmacology; Pralidoxime Compounds - chemistry; Pralidoxime Compounds - pharmacology; Structure-Activity Relationship
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.6b00198

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.