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Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study.


ABSTRACT: 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 (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) 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 HssAChE.

SUBMITTER: da Silva JAV 

PROVIDER: S-EPMC7072650 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study.

da Silva Jorge Alberto Valle JAV   Pereira Ander Francisco AF   LaPlante Steven R SR   Kuca Kamil K   Ramalho Teodorico Castro TC   França Tanos Celmar Costa TCC  

Biomolecules 20200127 2


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)  ...[more]

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