7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

• Klíčová slova
• 7-MEOTA-4-PA, Acetylcholinesterase, NAC, VX, molecular modeling,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• organothiofosforové sloučeniny chemie   farmakologie   MeSH
• oximy chemie   farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• pyridiny chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-methoxytacrine-4-pyridinealdoxime MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• obidoxim chlorid MeSH
• organothiofosforové sloučeniny MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridine-4-aldoxime MeSH Prohlížeč
• pyridiny MeSH
• VX MeSH Prohlížeč

The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood⁻brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies.

• Klíčová slova
• Ellman’s method, TOPSIS-AHP, acetylcholinesterase, molecular modeling, multicriteria decision making, neutral oxime,
• MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• erytrocyty účinky léků   enzymologie   MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• oximy chemie   farmakologie   MeSH
• paraoxon chemie   farmakologie   MeSH
• reaktivátory cholinesterasy chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• oximy MeSH
• paraoxon MeSH
• reaktivátory cholinesterasy MeSH

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator's molecule are described.

• Klíčová slova
• acetylcholinesterase, in vitro, molecular docking, organophosphate, oxime, reactivation,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie s uhlíkem 13C MeSH
• organofosforové sloučeniny toxicita   MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• reaktivátory cholinesterasy chemická syntéza   chemie   farmakologie   MeSH
• rekombinantní proteiny metabolismus   MeSH
• simulace molekulového dockingu * MeSH
• techniky in vitro MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• organofosforové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• rekombinantní proteiny MeSH