Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme-the phosphotriesterase. This one is characteristic of some soils' microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure-paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions.

• Klíčová slova
• bioremediation, molecular modeling, organophosphorus compounds, phosphotriesterase,
• MeSH
• biodegradace * MeSH
• chemická válka MeSH
• hydrolýza MeSH
• insekticidy chemie   metabolismus   MeSH
• lidé MeSH
• organofosforové sloučeniny chemie   metabolismus   MeSH
• paraoxon analogy a deriváty   chemie   MeSH
• pesticidy chemie   toxicita   MeSH
• půda chemie   MeSH
• pyrrolidiny chemie   MeSH
• veřejné zdravotnictví MeSH
• zemědělství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ethylparaoxon MeSH Prohlížeč
• insekticidy MeSH
• N-ethylmercapto-3-4-dihydroxy-2-hydroxymethylpyrrolidine MeSH Prohlížeč
• organofosforové sloučeniny MeSH
• paraoxon MeSH
• pesticidy MeSH
• půda MeSH
• pyrrolidiny MeSH

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC50) and their reactivation potency (R50) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC50 of K378 and K727 were comparable (0.9 and 1 µM, respectively) but orders of magnitude lower than comparators. R50 values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. The in silico and in vitro studies described allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use.

• Klíčová slova
• K-27, K378, K727, Oximes, organophosphates, paraoxon-ethyl, pralidoxime,
• MeSH
• acetylcholinesterasa krev   chemie   MeSH
• antidota chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemie   metabolismus   toxicita   MeSH
• GPI-vázané proteiny antagonisté a inhibitory   krev   chemie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• otrava organofosfáty krev   farmakoterapie   enzymologie   MeSH
• oximy chemie   metabolismus   farmakologie   MeSH
• paraoxon analogy a deriváty   chemie   metabolismus   toxicita   MeSH
• pralidoximové sloučeniny chemie   metabolismus   farmakologie   MeSH
• pyridinové sloučeniny chemie   metabolismus   farmakologie   MeSH
• reaktivátory cholinesterasy chemie   metabolismus   farmakologie   MeSH
• simulace molekulového dockingu * MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• 1-(3-phenylpropyl)-4-hydroxyiminomethylpyridinium MeSH Prohlížeč
• 4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide MeSH Prohlížeč
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• antidota MeSH
• cholinesterasové inhibitory MeSH
• ethylparaoxon MeSH Prohlížeč
• GPI-vázané proteiny MeSH
• naphthylene-2,7-diyl-bis(2-hydroxyiminomethylpyridinium) MeSH Prohlížeč
• oximy MeSH
• paraoxon MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH