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

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

Jorge Alberto Valle da Silva  1 , Ander Francisco Pereira  2 , Steven R LaPlante  3 , Kamil Kuca  4 , Teodorico Castro Ramalho  2   5 , Tanos Celmar Costa França  3   4   5
Affiliations

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

Jorge Alberto Valle da Silva et al. Biomolecules. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representation of the near attack conformation (NAC) obtained before for deprotonated 2-PAM inside VX-inhibited HssAChE after docking and molecular-dynamics (MD) simulations [20].
Figure 2
Figure 2
Energy profile obtained through the quantum mechanics (QM)/molecular mechanics (MM) methodology.
Figure 3
Figure 3
QM system (coloured atoms) after geometry optimization of the NAC frame.
Figure 4
Figure 4
TS structure (QM system = coloured atoms) for the reactivation reaction of VX-inhibited HssAChE by deprotonated 2-PAM.
Figure 5
Figure 5
Activation energy profile for the formation of the complex 2-PAM/VX/Ser203.
See this image and copyright information in PMC

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