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

Biomolecules. 2020 Jan 27;10(2):192. doi: 10.3390/biom10020192.

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.

Keywords: 2-PAM; QM/MM method; VX; acetylcholinesterase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / drug effects*
  • Catalytic Domain
  • Humans
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Organothiophosphorus Compounds / pharmacology*
  • Pralidoxime Compounds / chemistry
  • Pralidoxime Compounds / pharmacology*
  • Protons
  • Quantum Theory
  • Serine / chemistry

Substances

  • Organothiophosphorus Compounds
  • Pralidoxime Compounds
  • Protons
  • Serine
  • VX
  • Acetylcholinesterase
  • pralidoxime