Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

• MeSH
• algoritmy MeSH
• chemie farmaceutická MeSH
• kvantová teorie MeSH
• lidé MeSH
• proteinkinasy aktivované AMP metabolismus   chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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

This review article aims to address the main features of breast cancer. Thus, the general aspects of this disease have been shown since the first evidence of breast cancer in the world until the numbers today. In this way, there are some ways to prevent breast cancer, such as the woman's lifestyle (healthy eating habits and physical activities) that helps to reduce the incidence of this anomaly. The first noticeable symptom of this anomaly is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer are discovered when the woman feels a lump being present and about 90% of the cases, the cancer is noticed by the woman herself. Currently, the most used method for the detection of cancer and other injuries is the Magnetic Resonance Imaging (MRI) technique. This technique has been shown to be very effective, however, for a better visualization of the images, Contrast Agents (CAs) are used, which are paramagnetic compounds capable of increasing the relaxation of the hydrogen atoms of the water molecules present in the body tissues. The most used CAs are Gd3+ complexes, although they are very efficient, they are toxic to the organism. Thus, new contrast agents have been studied to replace Gd3+ complexes; we can mention iron oxides as a promising substitute.

• MeSH
• kontrastní látky * MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• nádory prsu * diagnostické zobrazování   MeSH
• voda MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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

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