Research of efficient reactivation agents of inhibited AChE is still challenging as dysfunction of AChE due to inhibition by organophosphorus (OP) compound is a major threat. We choose to look at tabun since it is one of the more potent nerve agents, and the AChE-tabun complex is very difficult to reactivate. In order to study the interaction between AChE and tabun from a theoretical point of view, we used a QM/MM methodology. First, we defined our model on acetylcholine which is the natural substrate of AChE. We showed that AChE is a very flexible enzyme, and thus that it is difficult to study it using theoretical chemistry. Then we studied tabun inhibition of AChE to underline the importance of tabun structure on its reactivity in the active site, and particularly the steric influence of N-dimethyl group. Finally we explored the importance of the mechanism (one or two steps) on the reactivation. Thanks to our results, we designed a new reactivator, which was synthetised and tested in vitro. Unfortunately, this new reactivator was not efficient against tabun poisoning because of physico-chemical parameters that we cannot take into account in our methodology. Thus we succeeded in developing an efficient theoretical model to describe interactions between AChE and different substrates.
