Dépôt numérique

Molecular modeling of Mannich phenols as reactivators of human acetylcholinesterase inhibited by A-series nerve agents

Vieira, Leandro A; Almeida, Joyce S F D; De Koning, Martijn C; Laplante, Steven ORCID logoORCID: https://orcid.org/0000-0003-2835-5789; Borges, Itamar et Franca, Tanos Celmar Costa (2023). Molecular modeling of Mannich phenols as reactivators of human acetylcholinesterase inhibited by A-series nerve agents Chemico-biological interactions , vol. 382 , nº 110622. pp. 1-13. DOI: 10.1016/j.cbi.2023.110622.

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The A-series is the most recent generation of chemical warfare nerve agents (CWA) which act directly on the inhibition of the human acetylcholinesterase (HssAChE) enzyme. These compounds lack accurate experimental data on their physicochemical properties, and there is no evidence that traditional antidotes effectively reactivate HssAChE inhibited by them. In the search for potential antidotes, we employed virtual screening, molecular docking, and molecular dynamics (MD) simulations for the theoretical assessment of the performance of a library of Mannich phenols as potential reactivators of HssAChE inhibited by the Novichok agents A-230, A-232, and A-234, in comparison with the commercial oximes pralidoxime (2-PAM), asoxime (HI-6), trimedoxime (TMB-4), and obidoxime. Following the near-attack conformation (NAC) approach, our results suggest that the compounds assessed would face difficulties in triggering the proposed nucleophilic in-line displacement mechanism. Despite this, it was observed that certain Mannich phenols presented similar or superior results to those obtained by reference oximes against A-232 and A-234 model, suggesting that these compounds can adopt more favourable conformations. Additional binding energy calculations confirmed the stability of the model/ligands complexes and the reactivating potential observed in the molecular docking and MD studies. Our findings indicate that the Mannich phenols could be alternative antidotes and that their efficacy should be evaluated experimentally against the A-series CWA.

Type de document: Article
Mots-clés libres: Molecular modeling; Near-attack conformation; Nerve agents; Non-oximes; Novichok.
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 07 déc. 2023 21:05
Dernière modification: 07 déc. 2023 21:05
URI: https://espace.inrs.ca/id/eprint/13677

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