Accession Number : AD1034446

Title :   beta-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase

Descriptive Note : OSTP Journal Article

Corporate Author : Biotechnology High Performance Computing Frederick United States

Personal Author(s) : Khavrutskii,Ilja V ; Wallqvist,Anders

Full Text :

Report Date : 08 Feb 2017

Pagination or Media Count : 6

Abstract : 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 mechanical/molecular 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.

Descriptors :   NERVE AGENTS , central nervous system , alkylating agents , neutral amino acids , 1ring heterocyclic compounds , computational chemistry , nerve agents , simulations , amines , alcohols , neurology , ENZYMES , peripheral nervous system , chemical reactions

Subject Categories : Biochemistry

Distribution Statement : APPROVED FOR PUBLIC RELEASE