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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F23%3A50020540" target="_blank" >RIV/62690094:18470/23:50020540 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0009279723002892?pes=vor" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0009279723002892?pes=vor</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.cbi.2023.110622" target="_blank" >10.1016/j.cbi.2023.110622</a>

Result language

angličtina

Original language name

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

Original language description

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. © 2023 Elsevier B.V.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30108 - Toxicology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Chemico-biological interactions

ISSN

0009-2797

e-ISSN

1872-7786

Volume of the periodical

382

Issue of the periodical within the volume

September

Country of publishing house

IE - IRELAND

Number of pages

13

Pages from-to

"Article number: 110622"

UT code for WoS article

001047362700001

EID of the result in the Scopus database

2-s2.0-85165249492