Molecular dynamics of the interaction of pralidoxime and deazapralidoxime with acetylcholinesterase inhibited by the neurotoxic agent tabun

Efficient acetylcholinesterase reactivators are fundamental for the development of antidotes against poisoning by neurotoxic pesticides and chemical warfare agents. However, the mechanism of the reactivation reaction and the structural characteristics of the known reactivators are poorly understood. In order to study the dynamic behavior and the effect of the antidote net charge in the reactivation of this enzyme, we carried out a molecular dynamics study of human acetylcholinesterase inhibited by tabun in complex with the antidote pralidoxime and with its deaza analogues in the neutral and anionic forms. Results show that the positive charge of pralidoxime is important for its admission and permanence inside the active site. Also, the analogues, unlike pralidoxime, when forced inside the active site, move away from the phosphorilated serine residue of the enzyme and are repelled by the electrostatic potential at the entrance of the channel that conducts to the active site.