| Summary: | In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (<i>Homo sapiens sapiens</i>) acetylcholinesterase (<i>Hss</i>AChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition−elimination steps, starting with a nucleophile bimolecular substitution (S<sub>N</sub>2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of <i>Hss</i>AChE.
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