In silico study on aging and reactivation processes of tabun conjugated AChE

Abstract

We have examined the aging and reactivation mechanisms of the tabun-conjugated AChE using MP2/6-31 + G*//M05-2X/6-31G* level of theory. The activation barriers have been calculated for the aging process considering both O-dealkylation and deamination (P–N anti deamination and rearrangement–deamination) pathways. The aging process is reported as a competing reaction with the reactivation process as the deamination/dealkylation process occurs rapidly with a half-life (<1–30 min) depending on the enzyme. To avoid the aging process, suitable reactivators are in demand to restore the function of AChE. 3-Hydroxy-2-pyridylamide oxime (amidoxime (I)) has been chosen as the reactivator to examine the competing aging process of tabun-conjugated AChE. The energy of activation predicted for the reactivation of tabun-conjugated AChE by 3-hydroxy-2-pyridylamide oxime (amidoxime (I)) is 2.3 kcal mol⁻¹, which is lower than the activation energies calculated for studied aging processes. The structural analysis from the docking studies of the model oxime (I) and the oximes used for the reactivation of tabun-inhibited AChE reveals that the peripheral sites play an important role for the efficacy of drugs. The reactivator is stabilized by π–π interaction with Tyr337, edge to face (C–H⋯π) interaction with Trp86 residues and hydrogen bonding interactions with His447 and alkoxy oxygen of tabun in the active site of tabun-inhibited AChE. Such stabilization from surrounding aromatic residues is helpful for the favourable orientation of the oxime group towards the phosphorus centre of tabun. The calculated Log P value indicates that the neutral reactivator can effectively penetrate through the blood brain barrier. The calculated results show that the neutral antidotes can effectively reactivate the tabun-inhibited AChE prior to its aging process.