Cover Feature: Screening for Improved Nerve Agent Simulants and Insights into Organophosphate Hydrolysis Reactions from DFT and QSAR Modeling (Chem. Eur. J. 39/2019)

Abstract

The effective detoxification of chem. warfare agents, specifically nerve agents, is a pressing issue in the modern world. Due to the high toxicity of these mols., simulants are often used in expts. 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. D. functional theory calcns. were performed on the alk. hydrolysis of over 100 organophosphate mols. 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 degrdn. mechanism. This screening highlighted 5 mols. that have nearly identical reaction barriers to the actual agents, while being far less toxic. Quant. structure-activity relationship (QSAR) models were also derived to det. the most significant mol. descriptors for describing the hydrolysis free energy barriers of these reactions. The optimal QSAR model was subjected to a thorough statistical anal. and validation procedure to confirm its predictive capacity, showing excellent quant. 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. [on SciFinder(R)]