Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

• Klíčová slova
• chemical/biological warfare agents, ligand-based virtual screening, molecular dynamics, ricin, ricin inhibitors,
• MeSH
• algoritmy MeSH
• chemické bojové látky chemie   MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární struktura MeSH
• objevování léků MeSH
• ricin antagonisté a inhibitory   chemie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chemické bojové látky MeSH
• ligandy MeSH
• ricin MeSH

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

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

• Klíčová slova
• acetylcholinesterase, antidotes, drug design, neutral oximes, pesticides,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Electrophorus metabolismus   MeSH
• enzymové reaktivátory chemie   farmakologie   MeSH
• molekulární struktura MeSH
• oximy chemie   farmakologie   MeSH
• paraoxon toxicita   MeSH
• rybí proteiny metabolismus   MeSH
• techniky in vitro MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• enzymové reaktivátory MeSH
• oximy MeSH
• paraoxon MeSH
• rybí proteiny MeSH