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

Jorge Alberto Valle Da Silva,Tanos Celmar Costa França,Ander Francisco Pereira,Kamil Kuca,Steven R Laplante,Teodorico Castro Ramalho

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.

Highlights

Studies on the high toxicity of insecticides and pesticides to mammals led to the development of organophosphorous (OP) nerve agents
The hydrogen atom of His447, which may stabilize the Ser203 after HssAChE reactivation (Figure 1), was 7.84 Å away from the O-atom of Ser203 (Figure 3)
The results of classical MD simulations reported in our former study [20] were shown to be a good starting point for the quantum mechanical (QM) calculations performed in this work, resulting in a comprehensive combined QM/molecular mechanics (MM) approach to study the reactivation mechanism of OP-inhibited AChE

Summary

Introduction

Studies on the high toxicity of insecticides and pesticides to mammals led to the development of organophosphorous (OP) nerve agents. RAessulat, result, the theoretical efficiency of the deprotonated 2-PAM to reactivate the VX-inhibited HssAChE was confirmed. The TS geometry was characterized and the reactivation energy barrier to achieve it was determined, to what was previously described by Driant et al [36]. Btihomeotlheceuolerse2t0i2c0a, l10e,ffi19c2iency of the deprotonated 2-PAM to reactivate the VX-inhibited HssAChE3wofa8s confirmed.

Results

Conclusion