Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates

Abstract

The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood−brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

“…Previously, literature that reported on the MDS of sarin-AChE complex, shows that sarin-AChE presents greater position variation from the starting system configuration (de Souza et al, 2020). Sarin can affect the whole protein structure due to its interaction with the AChE active site's.…”

“…In order to reactivate the AChE-OP complex, a reactivator should exhibit good affinity and reactivity. Good affinity derived from these physicochemical features such as; electrostatic effects, hydrophobic interactions and steric compatibility, while reactivity derived from the nucleophilicity of the oxime or non-oxime moiety (de Souza et al, 2020). Hence, the structure and the position of the reactivator also affect the reactivation potential.…”

“…For years, HI6 and 2-PAM have been the leading oximes due to their competency to reactivate OP-inhibited AChE (Ajami & Rebek, 2013;Mercey et al, 2012a;Kuca et al, 2013). However, there are limitations of these oximes due to their quaternary nitrogen charge, which lead to the inefficiency to penetrate the blood-brain barrier (de Souza et al, 2020;Radic et al, 2013;Radic et al, 2012;Sit et al, 2011;Kovarik et al, 2013;Tang et al, 2013). Subsequently, several attempts have been performed to find potential non-ionic oximes.…”

A Comprehensive Review of Cholinesterase Modeling and Simulation

“…Monte Carlo calculations by Veselinovic et al of AChE-sarin reactivation reiterated that pyridinium oximes are decent antidotes [ 160 ]. A more recent study of charged and uncharged oximes by de Souza et al compared these species with VX- and GB-poisoned AChE: while charged oximes proved to outperform the uncharged oximes, it is also an unfortunate reality that charged oximes do not cross the blood-brain barrier very well, making physical intake of the better reactivator more difficult [ 161 ]. Despite this setback, oximes are generally explored in more depth compared to pre-exposure antidote carbamates because carbamates also change the AChE structure via carbamylation [ 162 ].…”

Transitioning from Oxime to the Next Potential Organophosphorus Poisoning Therapy Using Enzymes

“…e development progress of the BBB-penetrating oxime is slow, and there are no reported novel compounds that are suitable for advanced development or into clinical use [36]. e searching and exploration of enhanced uncharged oximes with the ability to reactivate human AChE are still needed [60,61]. Recently, seven candidates of uncharged acetamido bis-oximes have been synthesized as reactivators [62].…”