Screening for Improved Nerve Agent Simulants and Insights into Organophosphate Hydrolysis Reactions from DFT and QSAR Modeling

Abstract

The effective detoxification of chemical warfare agents, specifically nerve agents, is a pressing issue in the modern world. Due to the high toxicity of these molecules, simulants are often used in experiments as substitutes for the agents. However, there is little reason to believe that the current simulants used in the literature are optimal predictors of nerve agent reactivity. Density functional theory calculations were performed on the alkaline hydrolysis of over 100 organophosphate molecules to identify improved simulants for the G‐series nerve agents soman and sarin, based on low toxicity and similarity to nerve agent hydrolysis energetics and degradation mechanism. This screening highlighted 5 molecules that have nearly identical reaction barriers to the actual agents, while being far less toxic. Quantitative structure–activity relationship (QSAR) models were also derived to determine the most significant molecular descriptors for describing the hydrolysis free energy barriers of these reactions. The optimal QSAR model was subjected to a thorough statistical analysis and validation procedure to confirm its predictive capacity, showing excellent quantitative and ranking accuracy. It was further shown that the model trained on G‐series agents can reliably predict energetics for other organophosphate classes as well, including VX. Through these computational insights, experimentalists may be aided in accurately and safely studying these reactions with less toxic simulants.

Theoretical study on the toxicity of ‘Novichok’ agent candidates

“…The catalytic mechanism of acetylcholinesterase is based on the formation of a tetrahedral acyl-enzyme intermediate, and phosphate-enzyme intermediate for the chemical agent's reactions. Although extensive structural and energy calculations on the transition state of each reaction pathway would be another way of estimating the kinetic parameters, as indicated in several other reports [24,25], charge on the central phosphorus atom is used for evaluating the reactivity of the nerve agent. Therefore, charge in phosphorus atom in organophosphorus compound would be used for toxicity comparison in the limited conditions.…”

Identification of organophosphorus simulants for the development of next-generation detection technologies

“…[21][22][23][24] Recently, work undertaken by Snurr and Mendonca, has shown that density functional theory (DFT) can be used to study the mechanism of OP hydrolysis, which has resulted in the development of a quantitative structure activity relationship (QSAR) model that enables the identification of appropriate OP CWA simulants for decontamination purposes. 25 However, when considering supramolecular technologies, the moiety target is often selective coordination of the polar PvO functionality. This chemical group, common to all OP CWAs, plays a significant role in both molecular surface coordination properties and reactivity.…”

“…Herein, we extend our prior work, which showed that simple, low level computational modelling may be used to predict hydrogen bond mediated aggregation events 26,27 and antimicrobial activity, 28 to identify appropriate OP CWA simulants for the development of supramolecular detection technologies, complementing the recent advances made in this area for hydrolysis siumulants. 25 Here, we hypothesised that neutral hydrogen bond donating receptors 1-4 ( Fig. 1) would form hydrogen bonded complexes with potential OP CWA simulants and, due to the structural simplicity of 1-4, the strength of the complex formed would depend on the properties associated with the principal hydrogen bond acceptor (HBA) group.…”

The Synthesis and Toxicological Characterization of Neurotoxic Chemical Agents Simulants

“…Their production, stockpiling and use are monitored by international organizations (Organization for the Prohibition of Chemical Weapons -OPCW) [9][10][11][12][13]. Neurotoxic chemical agents have the property of irreversibly inhibiting the erythrocytary acetylcholinesterase (AChE) [14][15][16][17][18]. The coupling reaction of the organophosphoric compounds at the level of the active situs of the enzyme is represented in fig.1, 2.…”

“…In fig. 3, the chemical structure of neurotoxic agents and their corresponding simulators are being shown [4,6,14,17,24]. The laboratory use of neurotoxic chemical agents is restricted, as they are extremely toxic substances.…”