In Silico Studies in Probing the Role of Kinetic and Structural Effects of Different Drugs for the Reactivation of Tabun-Inhibited AChE

Rabindranath Lo,Manoj K. Kesharwani,Nellore Bhanu Chandar,Aastha Jain,Israel Silman,Bishwajit Ganguly

doi:10.1371/journal.pone.0079591

Rabindranath Lo, Manoj K. Kesharwani

Open Access

https://doi.org/10.1371/journal.pone.0079591

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Abstract

We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O…H and N…H hydrogen bonding and C-H…π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.

Highlights

Acetylcholinesterase (AChE, EC 3.1.1.7), one of the most important enzymes in many living organisms, is responsible for the catalytic hydrolysis of neurotransmitter acetylcholine during nerve signal transmission [1,2,3]
The inhibition of AChE is mainly due to phosphylation of its active site serine hydroxyl group (Ser203 in hAChE), which is directly responsible for the catalytic hydrolysis of acetylcholine [11]
This study suggests that the positive charge of 2-PAM is important for its transportation to the active site of the enzyme

Summary

Introduction

Acetylcholinesterase (AChE, EC 3.1.1.7), one of the most important enzymes in many living organisms, is responsible for the catalytic hydrolysis of neurotransmitter acetylcholine during nerve signal transmission [1,2,3]. It is located at the neuromuscular junction and its catalytic triad (Ser203, Glu334 and His447 in hAChE) is mainly involved in the hydrolysis process [4,5]. Many organophosphorus compounds (OPs) react irreversibly with acetylcholinesterase, inhibiting its catalytic activity and its control over the central nervous system [6,7,8]. The aging of enzymes is irreversible in nature, prior to aging the nonaged enzyme can be reactivated by strong nucleophiles like oximes

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