Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: Hydroxylamine anion is predicted to be a better antidote with DFT calculations

Khan, Abdul Shafeeuulla; Lo, Rabindranath; Bandyopadhyay, Tusar; Ganguly, Bishwajit

doi:10.1016/j.jmgm.2011.04.009

Cited by 23 publications

(13 citation statements)

References 47 publications

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“…This charge analysis indicates that Ortho-7 will be a better nucleophile compared to 2-PAM [48]. The Wiberg bond index calculated for the P … O (Ortho-7) bond of C1b is found to be 0.008 au, which is higher than that of P … O (2-PAM) bond (0.005 au) for C1a , implying a stronger interaction in the reactant complex of Ortho-7 compared to 2-PAM [45], [46]. The calculated bonding parameters also suggest the preferable interaction of Ortho-7 with tabun-inhibited AChE (Figures 3 and 5).…”

Section: Resultsmentioning

confidence: 83%

“…We have further calculated the rate constants from the Gibbs free energies for the rate-determining steps of the reactivation processes. The first order rate constants for the reactivation reactions involving the neutral oximes DZP and 3-hydroxy-2-pyridinealdoxime are 1.9×10 10 s −1 and 5.1×10 9 s −1 , respectively [45], [46]. In the case of charged oximes, the rate constants values are relatively lower 4.0×10 7 s −1 and 4.1×10 3 s −1 for Ortho-7 and 2-PAM, respectively.…”

Section: Resultsmentioning

confidence: 93%

“…The oxime nucleophile 2-PAM attacks the phosphorus atom of nerve agent from the opposite side of serine residue (Figure 3). The reactivation process of tabun-inhibited AChE adducts with 2-PAM proceeds via an addition-elimination pathway with involvement of a trigonal bipyramidal intermediate (Figure 3) [45]–[47]. After complexation with tabun-inhibited enzyme the nucleophile 2-PAM becomes energetically more stable by 9.9 kcal/mol compared to the separated reactants (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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

Chandar

Kesharwani

et al. 2013

PLoS ONE

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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.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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

Chandar

Kesharwani

et al. 2013

PLoS ONE

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“…The reactivation of the sarin-serine adduct computed for both nucleophiles suggested similar trends, but reactivation with the hydroxylamine anion was found to be preferred by 4.1 kcal mol −1 over formoximate anion [36]. However, note that the calculated free energy of activation is 1.7 kcal mol −1 lower with the hydroxylamine anion compared to the formoximate anion.…”

Section: Reactivation With Hydroxylamine Anionmentioning

confidence: 79%

Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study

Khan

Ganguly

2011

J Mol Model

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Oximate anions are used as potential reactivating agents for OP-inhibited AChE because of they possess enhanced nucleophilic reactivity due to the α-effect. We have demonstrated the process of reactivating the VX-AChE adduct with formoximate and hydroxylamine anions by applying the DFT approach at the B3LYP/6-311 G(d,p) level of theory. The calculated results suggest that the hydroxylamine anion is more efficient than the formoximate anion at reactivating VX-inhibited AChE. The reaction of formoximate anion and the VX-AChE adduct is a three-step process, while the reaction of hydroxylamine anion with the VX-AChE adduct seems to be a two-step process. The rate-determining step in the process is the initial attack on the VX of the VX-AChE adduct by the nucleophile. The subsequent steps are exergonic in nature. The potential energy surface (PES) for the reaction of the VX-AChE adduct with hydroxylamine anion reveals that the reactivation process is facilitated by the lower free energy of activation (by a factor of 1.7 kcal mol(-1)) than that of the formoximate anion at the B3LYP/6-311 G(d,p) level of theory. The higher free energy of activation for the reverse reactivation reaction between hydroxylamine anion and the VX-serine adduct further suggests that the hydroxylamine anion is a very good antidote agent for the reactivation process. The activation barriers calculated in solvent using the polarizable continuum model (PCM) for the reactivation of the VX-AChE adduct with hydroxylamine anion were also found to be low. The calculated results suggest that V-series compounds can be more toxic than G-series compounds, which is in accord with earlier experimental observations.

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“…122 Li et al used QM/MM to determine that C−O bond scission in the AChE-tabun complex was caused by water attacking the tabun ethoxy group. 123 The reactivation process by the antidotes CH 2 NO − (formaldehyde oximate anion) or HLÖ-7 consists of three elemental steps: nucleophilic attack on the P atom by the antidote, dephosphorylation, and decomposition of the antidote−tabun complex.…”

Section: Industrial and Engineering Chemistry Researchmentioning

confidence: 99%

Computational Studies of Glycoside, Carboxylic Ester, and Thioester Hydrolase Mechanisms: A Review

Reilly

Rovira

2015

Ind. Eng. Chem. Res.

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This article is a review of computational work over the last ∼15 years to elucidate the catalytic mechanisms of three major enzyme classes: glycoside hydrolases, carboxylic ester hydrolases, and thioesterases. The mechanisms of glycoside hydrolases that both invert and retain the configuration of the anomeric carbon atom of the labile glycosidic bond are covered, as is the twisting of the glycosidic bond exerted by members of different glycoside hydrolase families. The hydrolytic mechanisms and substrate binding of five different carboxylic ester hydrolase classesacetylcholinesterases, butyrylcholinesterases, cocaine esterases, carboxylesterases, and triacylglycerol lipasesare addressed. Finally, the mechanism of members of a thioesterase family with HotDog tertiary structures is covered.

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Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: Hydroxylamine anion is predicted to be a better antidote with DFT calculations

Cited by 23 publications

References 47 publications

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

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

Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study

Computational Studies of Glycoside, Carboxylic Ester, and Thioester Hydrolase Mechanisms: A Review

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