Alzheimer's disease (AD) stands as the predominant contributor to dementia cases. The ongoing developments in our understanding of its pathogenesis have sparked the interest of researchers, driving them to explore innovative treatment approaches. Existing therapies incorporating cholinesterase inhibitors and/or NMDA antagonists have shown limited improvement in alleviating symptoms. This, in turn, highlights the urgency for the pursuit of more effective therapeutic options. Given the annual rise in the number of individuals affected by dementia, it is imperative to allocate resources and efforts towards the exploration of novel therapeutic options. This review aims to provide a comprehensive overview of the AD-related hypotheses, along with the computational approaches employed in research within each hypothesis. In this comprehensive review, the authors shed light on using various computational tools, including diverse case studies, in the pursuit of finding efficacious treatments for AD. The development of more sophisticated diagnostic techniques is crucial, enabling early detection and intervention in the battle against this challenging condition. The potential treatments investigated in this analysis are poised to assume ever more significant functions in both preventing and treating AD, ultimately enhancing the management of the condition and the overall well-being of individuals affected by AD.

• Keywords
• AD-related hypotheses, Alzheimer’s disease, amyloid-beta, computational approaches., neuroinflammation, tau protein,
• MeSH
• Alzheimer Disease * drug therapy   metabolism   diagnosis   MeSH
• Cholinesterase Inhibitors * chemistry   therapeutic use   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cholinesterase Inhibitors * MeSH

Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

• Keywords
• acetylcholinesterase, mechanistic studies, nerve agents, realkylation, resurrection,
• MeSH
• Acetylcholinesterase * chemistry   metabolism   MeSH
• Cholinesterase Inhibitors * chemistry   pharmacology   MeSH
• Indolequinones * chemistry   MeSH
• Kinetics MeSH
• Humans MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Thermodynamics MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase * MeSH
• Cholinesterase Inhibitors * MeSH
• Indolequinones * MeSH
• Ligands MeSH
• quinone methide MeSH Browser

Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, docking studies, molecular modeling, organophosphates, reactivation process, reactivators,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Phosphorus chemistry   MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Quantum Theory MeSH
• Humans MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Mice MeSH
• Organophosphates chemistry   MeSH
• Oximes chemistry   MeSH
• Protein Biosynthesis MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Sarin chemistry   MeSH
• Cluster Analysis MeSH
• Molecular Docking Simulation * MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Phosphorus MeSH
• Ligands MeSH
• Organophosphates MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH
• Sarin MeSH
• tabun MeSH Browser

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.

• Keywords
• acetylcholinesterase, computational methods, mechanistic studies, nerve agents, reactivation, trimedoxime,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes pharmacology   MeSH
• Cholinesterase Inhibitors metabolism   pharmacology   MeSH
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Nerve Agents chemistry   MeSH
• Organophosphorus Compounds chemistry   MeSH
• Oximes chemistry   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• Trimedoxime pharmacology   therapeutic use   MeSH
• Computational Biology methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors MeSH
• Nerve Agents MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Cholinesterase Reactivators MeSH
• Trimedoxime 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.

• Keywords
• acetylcholinesterase, new trends in reactivators, organophosphorus compounds, reactivation process, therapeutic potential,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• GPI-Linked Proteins metabolism   MeSH
• Humans MeSH
• Oximes chemistry   therapeutic use   MeSH
• Patents as Topic MeSH
• Cholinesterase Reactivators * chemistry   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• ACHE protein, human MeSH Browser
• GPI-Linked Proteins MeSH
• Oximes MeSH
• Cholinesterase Reactivators * 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.

• Keywords
• Alzheimer’s disease, antioxidants, cellular respiration, free radicals, oxidative stress,
• MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Amyloid beta-Peptides chemistry   metabolism   MeSH
• Antioxidants pharmacology   therapeutic use   MeSH
• Phosphorylation MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Oxidative Stress drug effects   MeSH
• tau Proteins chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Antioxidants MeSH
• tau Proteins MeSH