Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

Abstract

Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.

Aminoalkoxy‐substituted coumarins: Synthesis and evaluation for reactivation of inhibited human acetylcholinesterase

“…Such interactions have also been proposed for the binding modes in complexes of nonoxime [11] and oxime-based reactivators with inhibited AChE. [32,[35][36][37] The amino-alkoxy Liquid chromatography-mass spectrometry (LC-MS) analyses were carried out on an API2000 (Applied Biosystems) mass spectrometer coupled to an Agilent 1100 LC system using a Phenomenex Luna C18 column (Phenomenex; 50 × 2.0 mm, particle size 3 µm). The purity of the compounds was determined using the diode array detector (DAD) of the LC-MS instrument between 200 and 400 nm.…”

Broad‐Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve‐Agent‐Inhibited Acetylcholinesterase

“…The cleavage of the serine phosphoester has been proposed to proceed via a pentavalent intermediate, conceptually similar to a carbonyl addition, based on computational studies [75,76] and the conformation of the O‐alkyl moiety will influence the transition state energy and the accessibility of the phosphorus. It should be noted, however, that many computational studies focus either in the formation of the pre‐reactivation complex and binding of a peripheral site ligand, or on the details of the reactivation mechanism, yet rarely both [77,78] . We previously hypothesised that the reactivation of sarin‐AChE by HI‐6 depends on a conformational change of the O‐alkyl moiety of sarin and its interaction with Glu202 [58] .…”

“…It should be noted, however, that many computational studies focus either in the formation of the prereactivation complex and binding of a peripheral site ligand, or on the details of the reactivation mechanism, yet rarely both. [77,78] We previously hypothesised that the reactivation of sarin-AChE by HI-6 depends on a conformational change of the C) The deprotonated oxime is positioned towards the tabun-serine adduct. Oxygen, nitrogen, hydrogen, and phosphorus are displayed in red, blue, white, and orange, respectively.…”

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

“…Several studies based on molecular modeling and computer simulations appeared in the literature, to aid the experimental research in the efforts to design efficient oximes for the deactivation of a broad spectrum of OP compounds, as no single oxime available in the market can target the broad spectrum of OP derivatives [62][63][64]. For instance, docking studies and DFT calculations, conducted by Ramalho et al, demonstrated that the theoretical data aligned well with the experimental results, in the prediction of free energies of oximes that can further aid in designing effective oximes targeting AChE [65].…”