The nerve agents of the A-series are relatively recent chemical weapons with no antidote available yet. Once inside the human body, those chemicals act similarly to the classic nerve agents, by binding to the catalytic residue Serine 203 (Ser203) of human acetylcholinesterase (HssAChE) and thus preventing the proper function of this enzyme. However, there is no experimental evidence yet if the current antidotes for intoxication by nerve agents are also capable of restoring AChE inhibited by the nerve agents of the A-series. In order to launch some light on this issue, we used computational techniques (molecular docking, molecular dynamics and MM-PBSA interaction energy calculations) to assess the performances of the four currently available commercial oximes (2-PAM, HI-6, obidoxime and trimedoxime) when in contact with HssAChE inhibited by the agent A-242. Based on the near-attack conformation (NAC) criterion, our results suggest that the commercial oximes would have limited efficacy to reactivate the enzyme since they are not able to properly approach the adduct Ser203-A-242. Among those oximes, trimedoxime seems to be the most promising, since it showed lower values of energy in the MM-PBSA calculations, a higher stability inside the catalytic anionic center (CAS) of HssAChE, and was able to adopt a position closer to the NAC that could enable the reactivation mechanism.

Chemical Engineering Department Military Institute of Engineering Rio de Janeiro Brazil

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic; Institute of Chemical Biological Radiological and Nuclear Defense Rio de Janeiro RJ Brazil

Federal Institute of Education Science and Technonogy of Espírito Santo Units Vila Velha and Vitória ES Brazil; Federal University of Espirito Santo Unit Goiabeiras Vitoria Espírito Santo Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Rio de Janeiro Brazil; Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

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Are the current commercially available oximes capable of reactivating acetylcholinesterase inhibited by the nerve agents of the A-series?