@article{ref1,
title="Methyl scanning and revised binding mode of 2-pralidoxime, an antidote for nerve agent poisoning",
journal="ACS medicinal chemistry letters",
year="2020",
author="Gambino, Adriana and Burnett, James C. and Koide, Kazunori",
volume="11",
number="10",
pages="1893-1898",
abstract="Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood-brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.<p /> <p>Language: en</p>",
language="en",
issn="1948-5875",
doi="10.1021/acsmedchemlett.9b00586",
url="http://dx.doi.org/10.1021/acsmedchemlett.9b00586"
}