The authors‘ efforts to reproduce our results and to obtain further information about the action of 6-OxP-CD on cyclosarin is appreciated. However, contrary to the authors’ statement, we did consider other G-type nerve agents in our investigations, including soman (A. Bierwisch, M. Zengerle, H. Thiermann, S. Kubik, F. Worek "Detoxification of alkyl methylphosphonofluoridates by an oxime-substituted β-cyclodextrin - an in vitro structure-activity study" Toxicol. Lett. 2014, 224, 209-214; 10.1016/j.toxlet.2013.10.024). We already showed in the corresponding article that soman degradation is significantly slower in the presence of 6-OxP-CD than cyclosarin degradation. We wrote in this context: "… of all the sarin derivatives investigated soman is detoxified with the lowest rate although the pinacolyl residue is expected to efficiently interact with β-CD. neo-Pentylsarin, which lacks the methyl group at the carbon atom bound to the alcohol oxygen with respect to soman, is detoxified considerably faster. In the case of soman it is likely that structural parameters of the complex (e.g. incomplete inclusion of the alcohol residue into the CD cavity caused by steric effects of the methyl group next to the oxygen atom) are responsible for inhibition of the reaction between the phosphonate and a nucleophilic group on the ring." It is interesting to see that the molecular dynamics simulations described in this manuscript appear to indicate that soman is included into the β-CD with the wrong orientation to be efficiently detoxified.
It is worth pointing out that mechanistic studies have also already been performed by us, the results of which were published in two articles (A. Kranawetvogl, S. Müller, S. Kubik, H. Spruit, H. Thiermann, F. Worek, D. Noort, G. Reiter "Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro" Toxicol. Lett. 2015, 239, 41-52; 10.1016/j.toxlet.2015.08.007; A. Bierwisch, M. Koller, F. Worek, S. Kubik "Pathways for the reactions between neurotoxic organophorphorous compounds and oximes or hydroxamic acids" Eur. J. Org. Chem. 2016, 5831-5838; 10.1002/ejoc.201601053). Our results, which were partly obtained by similar 31P NMR spectroscopic studies as those performed by the authors, led to a relatively detailed mechanistic picture of the action of 6-OxP-CD on GF.
Finally, we wrote in an article in which we reported a compound that is able to detoxify VX "V-type nerve agents are poor substrates for cyclodextrins because of their protonated side chain amino groups and, hence, polar nature at physiological pH values," (C. Schneider, A. Bierwisch, M. Koller, F. Worek, S. Kubik "Detoxification of VX and other V-type nerve agents in water at 37 °C and pH 7.4 by substituted sulfonatocalix[4]arenes " Angew. Chem. Int. Ed. 2016, 55, 12668-12672; 10.1002/anie.201606881). This assumption was recently confirmed experimentally (C. Braga Barbosa, P. Gaß, D. J. Hamsch, S. Kubik "Characterization of the interaction of nerve agent mimics with selected synthetic receptors" Org. Mater. 2022, 4, 146-152; 10.1055/a-1939-6455). The inability of 6-OxP-CD to mediate VX detoxification is therefore more likely due to the lack of affinity for VX rather than to an inappropriate complex geometry. The discrepancy the authors’ and our interpretation could be due to the fact that they considered the neutral form of VX in their calculations, although VX preferentially exists at physiological pH in the cationic protonated form.