Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.
- MeSH
- acetylcholinesterasa chemie MeSH
- antidota * farmakologie terapeutické užití chemie MeSH
- cholinesterasové inhibitory toxicita MeSH
- organofosforové sloučeniny MeSH
- oximy terapeutické užití toxicita MeSH
- reaktivátory cholinesterázy * terapeutické užití toxicita MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time-space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.
- MeSH
- chinoliny chemie terapeutické užití MeSH
- COVID-19 MeSH
- farmakoterapie COVID-19 MeSH
- počítačová simulace MeSH
- preklinické hodnocení léčiv MeSH
- SARS-CoV-2 chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- teorie funkcionálu hustoty MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota farmakologie MeSH
- cholinesterasové inhibitory metabolismus farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- nervová bojová látka chemie MeSH
- organofosforové sloučeniny chemie MeSH
- oximy chemie MeSH
- reaktivátory cholinesterázy chemie farmakologie MeSH
- trimedoxim farmakologie terapeutické užití MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Halogenated phenols, such as 2,4-dichlorophenol (2,4-DCP) and 4-bromophenol (4-BP) are pollutants generated by a various industrial sectors like chemical, dye, paper bleaching, pharmaceuticals or in an agriculture as pesticides. The use of Horseradish peroxidase (HRP) in the halogenated phenols treatment has already been mentioned, but it is not well understood how the different phenolic substrates can bind in the peroxidase active site nor how these specific interactions can influence in the bioremediation potential. In this work, different removal efficiencies were obtained for phenolic compounds investigated using HRP as catalyst (93.87 and 59.19% to 4BP and 2,4 DCP, respectively). Thus, to rationalize this result based on the interactions of phenols with active center of HRP, we combine computational and experimental methodologies. The theoretical approaches utilized include density functional theory (DFT) calculations, docking simulation and quantum mechanics/molecular mechanics (QM/MM) technique. Michaelis Menten constant (Km) obtained through experimental methodologies were 2.3 and 0.95 mM to 2,4-DCP and 4-BP, respectively, while the specificity constant (Kcat/Km) found was 1.44 mM-1 s-1 and 0.62 mM-1 s-1 for 4-BP and 2,4-DCP, respectively. The experimental parameters appointed to the highest affinity of HRP to 4-BP. According to the molecular docking calculations, both ligands have shown stabilizing intermolecular interaction energies within the HRP active site, however, the 4-BP showed more stabilizing interaction energy (-53.00 kcal mol-1) than 2,4-dichlorophenol (-49.23 kcal mol-1). Besides that, oxidative mechanism of 4-BP and 2,4-DCP was investigated by the hybrid QM/MM approach. This study showed that the lowest activation energy values for transition states investigated were obtained for 4-BP. Therefore, by theoretical approach, the compound 4-BP showed the more stabilizing interaction and activation energy values related to the interaction within the enzyme and the oxidative reaction mechanism, respectively, which corroborates with experimental parameters obtained. The combination between experimental and theoretical approaches was essential to understand how the degradation potential of the HRP enzyme depends on the interactions between substrate and the active center cavity of the enzyme.
Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- GPI-vázané proteiny metabolismus MeSH
- lidé MeSH
- oximy chemie terapeutické užití MeSH
- patenty jako téma MeSH
- reaktivátory cholinesterázy * chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Alzheimer's disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein chemie metabolismus MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- fosforylace MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- oxidační stres účinky léků MeSH
- proteiny tau chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata 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
INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia. Clinical progress in this pathogenesis field has drawn the attention of researchers, stimulating the investigation of novel treatment methods. Current therapies that deal with cholinesterase inhibitors and/or NMDA antagonists have shown a modest symptomatic potential, increasing the need for research into more efficient therapeutics. The goal of this review is to summarize the advances in, and the potential of, non-conventional therapies in AD treatment. Areas covered: In this review, the authors describe the current status of unusual therapies in AD treatment, evaluating the modern scientific contexts in which these therapies have been developed. The authors also highlight the usage of methylene blue, natural products, organophosphorus compounds, and Chinese medicine, along with the employment of nanotechnology. Expert opinion: The potential therapies discussed in this review will play increasingly important roles in the prevention and treatment of AD, improving disease management and quality of life for AD patients. Given the annual increasing number of people with dementia, it is crucial to invest in the search for novel therapeutics. In addition, more sophisticated diagnosis techniques are also essential, to allow for an early diagnosis and treatment.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- methylenová modř terapeutické užití MeSH
- nanotechnologie * MeSH
- organofosforové sloučeniny terapeutické užití MeSH
- tradiční čínská medicína * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy 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
