beta-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase
OSTP Journal Article
Biotechnology High Performance Computing Frederick United States
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Organophosphate nerve agents inhibit the enzyme acetyl cholinesterase AChE, which is involved in nerve signal transduction, by forming covalent adducts with its catalytic serine residue. AChE adducts with soman and sarin nerve agents undergo dealkylation, a process known as aging, within a few minutes and a few hours, respectively. This transformation is detrimental because it precludes reactivation of AChE with known oxime-based antidotes. Here, we designed a beta-aminoalcohol molecule for aged AChE reactivation, using a multi-tiered computational approach. This approach includes high-quality quantum mechanicalmolecular mechanical calculations, providing reliable reactivation steps and energetics. The calculations suggest that the designed beta-aminoalcohol can selectively reactivate aged sarin-soman-inhibited AChE. Furthermore, unlike existing antidotes, the designed beta-aminoalcohol lacks a permanent change, making it potentially active in the central nervous system. The mechanistic insights of this study can help guide the development of new AChE reactivators with improved access to the central nervous system.