Molecular modelling studies on the interactions of 7-methoxytacrine-4-pyridinealdoxime with VX-inhibited human acetylcholinesterase: a near attack approach to assess different spacer-lengths

Abstract

The novel prophylactic agent 7-methoxytacrine-4-pyridinealdoxime is a hybrid compound formerly designed to keep acetylcholinesterase resistant to organophosphates by reactivating it in case of intoxication by such inhibitors. In rational design, a 5-carbon length-spacer hybrid compound was synthesized to evaluate its inhibitory and reactivation capabilities. In this work, theoretical results were achieved through molecular modelling techniques, taking for granted the enzymatic reactivation reaction through nucleophilic substitution. Based on the near attack conformation approach, docking studies were performed to assess the spacer-length from 1 to 10 carbons long of a series of analogues of 7-methoxytacrine-4-pyridinealdoxime. Consequently, the hybrids with length-spacer of 4 and 5 carbons long were the best assessed and subsequently subjected to further molecular dynamics simulations, complemented by Poisson-Boltzmann surface area calculations. As a result, intermolecular interactions with the different binding sites inside human acetylcholinesterase were elucidated. Besides, thermodynamics and kinetics concepts pointed to the 4-carbon linker as optimum for enzymatic reactivation. Further studies, based on quantum mechanics in conjunction with molecular mechanics, were recommended to the presented near attack conformations to achieve more thermodynamics results between the hybrids with 4- and 5-carbon linkers, like values of activation energy for the reactivation reaction. All of those in silico evaluations could be considered as a set of tools for theoretically investigate novel enzymatic reactivators with different shape of spacers.