Molecular and physical prerequisites for rational design of efficient antidotes for nerve agent toxicity

The potential use of chemical warfare, such as organophosphate nerve agents (OPNAs), in assassinations and terror attacks, is a significant societal threat.

OPNAs (e.g. sarin, tabun and novichok) are acute toxic due to their fast covalent inhibition of the enzyme acetylcholinesterase (AChE), which lead to cholinergic crisis and death.

Today, there is a lack of satisfying therapeutic treatments of nerve agent intoxications.A broad spectrum antidote with satisfying clinical properties to treat OPNA toxicity is of great need.

We aim to develop predictive modelling of antidotes (also called reactivators) for nerve agent toxicity that can be used in chemistry research labs and in drug discovery.

We will create computational approaches to simulate the reaction mechanism of the reactivation of the OPNA-inhibited AChE by oxime reactivators. It will be at a molecular and physical organic chemistry level, and be linked to reactivation kinetics data.

Our plan is to: (A) Simulate and elucidate the first step of the reactivation using molecular dynamics simulations and quantum mechanics (QM). (B) Calculate energy profiles of the chemical reactivation reaction using QM together with molecular mechanics (QM/MM). (C) Use the predictive schemes based on the simulations, elucidations and empirical data to design new oxime antidotes, which will be made and evaluated by organic synthesis and biophysical assays.