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.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• lidé MeSH
• nervová bojová látka * toxicita   MeSH
• organofosfáty MeSH
• oximy chemie   farmakologie   MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterázy * farmakologie   MeSH
• simulace molekulového dockingu MeSH
• trimedoxim farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

• MeSH
• COVID-19 * MeSH
• cysteinové endopeptidasy MeSH
• farmakoterapie COVID-19 MeSH
• inhibitory proteas MeSH
• koronavirové proteasy 3C MeSH
• léčivé přípravky MeSH
• lidé MeSH
• SARS-CoV-2 * MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH