Inhibitors of cholinesterases are a wide group of low molecular weight compounds with a significant role in the current pharmacology. Besides the pharmacological importance, they are also known as toxic compounds like military nerve agents. In the pharmacology, drugs for Alzheimer disease, myasthenia gravis and prophylaxis of poisoning by nerve agents can be mentioned as the relevant applications. Besides this, anti-inflammation and antiphrastic drugs are other pharmacological applications of these inhibitors. This review is focused on a survey of cholinesterase inhibitors with known or expected pharmacological impact and indications of their use. Recent literature with comments is provided here as well.
- MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- antiflogistika chemie farmakologie terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie patologie MeSH
- cholinesterasové inhibitory chemie metabolismus farmakologie terapeutické užití MeSH
- cholinesterasy chemie metabolismus MeSH
- insekticidy chemie MeSH
- lidé MeSH
- nervová bojová látka chemie metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Studies with oximes have been extensively developed to design new reactivators with better efficiency, and greater spectrum of action. In this study, we aimed to analyze the influence of the Carbamoyl group position change in two isomeric oximes, K203 and K206, on the reactivation percentage of Mus musculus Acetylcholinesterase (MmAChE), inhibited by different nerve agents. Theoretical calculations were performed to assess the difference for the oxime activity with inhibited AChE-complexes and the factors that govern this difference. Comparing theoretical and experimental data, it is possible to observe that this change between the oximes results in different reactivation percentage for the same nerve agent, due to the different interaction modes and activation energy for the studied systems.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- kvantová teorie MeSH
- myši MeSH
- nervová bojová látka chemie metabolismus MeSH
- organofosforové sloučeniny chemie metabolismus MeSH
- organothiofosforové sloučeniny chemie metabolismus MeSH
- oximy chemie MeSH
- racionální návrh léčiv MeSH
- reaktivátory cholinesterázy chemie metabolismus MeSH
- simulace molekulového dockingu MeSH
- termodynamika MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Organophosphorus compounds have been widely employed to the development of warfare nerve agents and pesticides, resulting in a huge number of people intoxicated annually, being a serious problem of public health. Efforts worldwide have been done in order to design new technologies that are capable of combating or even reversing the poisoning caused by these OP nerve agents. In this line, the bioremediation arises as a promising and efficient alternative for this purpose. As an example of degrading enzymes, there is the organophosphate-degrading (OpdA) enzyme from Agrobacterium radiobacter, which has been quite investigated experimentally due to its high performance in the degradation of neurotoxic nerve agents. This work aims to look into the structural and electronic details that govern the interaction modes of these compounds in the OpdA active site, with the posterior hydrolysis reaction prediction. Our findings have brought about data about the OpdA performance towards different nerve agents, and among them, we may realize that the degradation efficiency strongly depends on the nerve agent structure and its stereochemistry, being in this case the compound Tabun the one more effectively hydrolyzed. By means of the chemical bonds (AIM) and orbitals (FERMO) analysis, it is suggested that the initial reactivity of the OP nerve agents in the OpdA active site does not necessarily dictate the reactivity and interaction modes over the reaction coordinate.
- MeSH
- Agrobacterium tumefaciens enzymologie MeSH
- bakteriální proteiny chemie metabolismus MeSH
- biodegradace * MeSH
- biokatalýza MeSH
- fosfatasy chemie metabolismus MeSH
- katalytická doména MeSH
- kvantová teorie MeSH
- lidé MeSH
- nervová bojová látka chemie metabolismus MeSH
- sarin chemie metabolismus MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Bispyridinium oximes with one (K865, K866, K867) or two (K868, K869, K870) ortho-positioned chlorine moiety, analogous to previously known K027, K048 and K203 oximes, and potent reactivators of human acetylcholinesterase (AChE) inhibited by nerve agents, were tested in the reactivation of human butyrylcholinesterase (BChE) inhibited by sarin, cyclosarin, VX, and tabun. A previously highlighted AChE reactivator, dichlorinated bispyridinium oxime with propyl linker (K868), was tested in more detail for reactivation of four nerve agent-BChE conjugates. Its BChE reactivation potency was showed to be promising when compared to the standard oximes used in medical practice, asoxime (HI-6) and pralidoxime (2-PAM), especially in case of sarin and tabun. This finding could be used in the pseudo-catalytic scavenging of the most nerve agents due to its cumulative capacity to reactivate both AChE and BChE.
- MeSH
- aktivace enzymů účinky léků MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie metabolismus MeSH
- halogenace MeSH
- kinetika MeSH
- lidé MeSH
- nervová bojová látka chemie metabolismus MeSH
- oximy chemie metabolismus farmakologie MeSH
- pyridinové sloučeniny chemie MeSH
- sarin chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.
- MeSH
- analýza hlavních komponent MeSH
- biodegradace MeSH
- katalytická doména MeSH
- kvantová teorie * MeSH
- lidé MeSH
- nervová bojová látka chemie metabolismus MeSH
- organofosforové sloučeniny chemie metabolismus MeSH
- organothiofosforové sloučeniny chemie metabolismus MeSH
- pyrofosfatasy metabolismus MeSH
- sarin chemie metabolismus MeSH
- simulace molekulového dockingu * MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
