scholarly journals Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2058
Author(s):  
Georgi Stavrakov ◽  
Irena Philipova ◽  
Atanas Lukarski ◽  
Mariyana Atanasova ◽  
Borislav Georgiev ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Ache Activity ◽  
Cognitive Impairments ◽  
Acetylcholinesterase Inhibitor ◽  
Symptomatic Treatment ◽  
Ache Inhibitor ◽  
Aromatic Fragment ◽  
Ache Inhibitors ◽  
Binding Core ◽  
Amyloid Cascade

Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.

scholarly journals Biomonitoring of Acetylcholinesterase (AChE) Inhibitor and the Association with Hypertension among Farmers in Bandung, Indonesia

2020 ◽  
Vol 12 (4) ◽  
pp. 325-332
Author(s):  
Mulyana Mulyana ◽  
Iwan Sugiarta ◽  
Lim Jen Fuk ◽  
Vani Nur Pratami ◽  
Dewi Yunia Fitriani ◽  
...  
Keyword(s):  
Risk Factors ◽  
Biological Sample ◽  
Ache Activity ◽  
Descriptive Analysis ◽  
Ache Inhibitor ◽  
Medical Team ◽  
Ache Inhibitors ◽  
Activity Frequency ◽  
History Of ◽  
Independent Risk Factors

BACKGROUND: The use of acetylcholinesterase (AChE) insecticides is still widely used by farmers in flower and agricultural centers. However, biological monitoring of farmers is still very rare in Indonesia. AChE inhibitors are reported to have toxic effects on various organs.METHODS: This study involved 120 subjects in Cihideung, Cikole and Pangalengan areas. All subjects have been interviewed, physically examined and biological sample taken by medical team. Descriptive analysis was performed to assess general conditions of the subjects and AChE erythrocyte activity enzyme at pseudo-baseline and the next 3 months from pseudo-baseline. Statistical analysis have been performed of the pseudo-baseline AChE erythrocyte activity with hypertension and history of exposures.RESULTS: The median value of pseudo-baseline AChE erythrocyte activity was 8.10 (1.3-14.25) U/g hematocrit. In the comparison between pseudo-baseline and 3 month from pseudo-baseline AChE activity, 7 respondents from 19 respondents (36.84%) had lower enzyme activity than 70% and the others subjects have higher activity value. AChE erythrocyte activity is associate with frequency of insecticide exposures. AChE erythrocyte activity (p=0.04; Exp (B)=2.937 CI 95%=1.049-8.224) and age (p=0.025; Exp (B)=3.872 CI 95%=1.180-12.703) are independent risk factors for hypertension in farmworker.CONCLUSION: AChE erythrocyte activity associated with frequency of insecticide exposures and hypertension among farmworkers.KEYWORDS: AChE erythrocyte activity, frequency of insecticide expsoures, hypertension

scholarly journals Computer-Aided Discovery of Pentapeptide AEYTR as a Potent Acetylcholinesterase Inhibitor

2020 ◽  
Vol 21 (1) ◽  
pp. 243
Author(s):  
Enade Perdana Istyastono ◽  
Vivitri Dewi Prasasty
Keyword(s):  
Acetylcholinesterase Inhibitor ◽  
Md Simulations ◽  
Structure Characterization ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Ic50 Value ◽  
Computer Aided ◽  
Acetylcholinesterase Enzyme ◽  
In Vitro Examination

One of the key targets in the drug development for potential Alzheimer’s disease (AD) therapeutics is the search for acetylcholinesterase enzyme (AChE) inhibitors. Very recently, a pentapeptide AEYTR was reported as a potential inhibitor for AChE. The peptide was identified in a retrospectively validated virtual screening campaign, which was subsequently followed by 10 ns molecular dynamics (MD) simulations. The study aimed to characterize the structure and identify in vitro of AEYTR peptide as a potent acetylcholinesterase inhibitor. This article presents the structure characterization and the in vitro examination of the peptide as an AChE inhibitor, followed by MD simulations for 100 ns. The results show that the pentapeptide is a potent AChE inhibitor with an IC50 value in the picomolar range and stabilizes the enzyme during MD simulations.

scholarly journals Antioxidant Activity of a Novel Acetylcholinesterase Inhibitor: In Vivo and Ex vivo Studies

2020 ◽  
Author(s):  
Rumiana Simeonova ◽  
Georgi Stavrakov ◽  
Irena Philipova ◽  
Mariyana Atanasova ◽  
Irini Doytchinova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Activity ◽  
Ex Vivo ◽  
Acetylcholinesterase Inhibitor ◽  
Toxicity Tests ◽  
Ache Inhibitor ◽  
Drug Candidate ◽  
Short Term ◽  
Ache Inhibitors

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer’s disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH). Haematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD50 of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves. In a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a perspective multitarget drug candidate for treatment of Alzheimer’s disease.

scholarly journals A Novel Application of Multiscale Entropy in Electroencephalography to Predict the Efficacy of Acetylcholinesterase Inhibitor in Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Ping-Huang Tsai ◽  
Shih-Chieh Chang ◽  
Fang-Chun Liu ◽  
Jenho Tsao ◽  
Yung-Hung Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acetylcholinesterase Inhibitor ◽  
Multiscale Entropy ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Biosignal Processing ◽  
The Difference ◽  
State Examination ◽  
Potential Tool

Alzheimer’s disease (AD) is the most common form of dementia. According to one hypothesis, AD is caused by the reduced synthesis of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) inhibitors are considered to be an effective therapy. For clinicians, however, AChE inhibitors are not a predictable treatment for individual patients. We aimed to disclose the difference by biosignal processing. In this study, we used multiscale entropy (MSE) analysis, which can disclose the embedded information in different time scales, in electroencephalography (EEG), in an attempt to predict the efficacy of AChE inhibitors. Seventeen newly diagnosed AD patients were enrolled, with an initial minimental state examination (MMSE) score of18.8±4.5. After 12 months of AChE inhibitor therapy, 7 patients were responsive and 10 patients were nonresponsive. The major difference between these two groups is Slope 2 (MSE6 to 20). The area below the receiver operating characteristic (ROC) curve of Slope 2 is 0.871 (95% CI = 0.69–1). The sensitivity is 85.7% and the specificity is 60%, whereas the cut-off value of Slope 2 is −0.024. Therefore, MSE analysis of EEG signals, especially Slope 2, provides a potential tool for predicting the efficacy of AChE inhibitors prior to therapy.

scholarly journals TSPO Expression Modulatory Effect of Acetylcholinesterase Inhibitor in the Ischemic Stroke Rat Model

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1350
Author(s):  
Yoo Sung Song ◽  
Sang Hee Lee ◽  
Jae Ho Jung ◽  
In Ho Song ◽  
Hyun Soo Park ◽  
...  
Keyword(s):  
Rat Model ◽  
Ache Activity ◽  
Inflammatory Responses ◽  
Acetylcholinesterase Inhibitor ◽  
Contralateral Side ◽  
Translocator Protein ◽  
Ache Inhibitor ◽  
Sprague Dawley ◽  
Brain Response

We performed in vivo PET imaging with 3-[18F]F-CP118,954 (1) for acetylcholinesterase (AChE) and [18F]fluoromethyl-PBR28-d2 (2) for translocator protein 18-kDa (TSPO) to investigate the inflammatory brain response after stroke. Imaging studies were performed in the middle cerebral artery occlusion (MCAO) Sprague-Dawley rat model for a period of three weeks. The percentage injected dose per tissue weight (%ID/g) of striatum of 1, and cortex of 2 were obtained, respectively. To trace the sequential inflammatory responses, AChE imaging of 1 was done on post-MCAO day 2, after giving cold PK-11195 for 1 day, and TSPO imaging of 2 was carried out on post-MCAO day 11, after giving donepezil for 10 days. AChE activity in the MCAO-lesioned side were significantly higher than that of the contralateral side on day one, and TSPO activity was highest on day 11. TSPO inhibitor, PK-11195 did not affect AChE activity on day two, while AChE inhibitor, donepezil significantly lowered TSPO binding on day 12. Our study demonstrates that AChE level is elevated in the early course of brain ischemia as a trigger for the inflammatory response, and TSPO level is elevated persistently throughout the post-ischemic injury in the brain. Also, the AChE inhibitor may be able to inhibit or delay neurotoxic inflammatory responses and serve as a beneficial treatment option.

scholarly journals Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Andrzej P. Herman ◽  
Dorota Tomaszewska-Zaremba ◽  
Marta Kowalewska ◽  
Aleksandra Szczepkowska ◽  
Małgorzata Oleszkiewicz ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Proinflammatory Cytokine ◽  
Preoptic Area ◽  
De Novo ◽  
Brain Parenchyma ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Reproduction Process ◽  
Hypothalamic Structure ◽  
Alpha 7

The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin—lipopolysaccharide (LPS; 400 ng/kg)—attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p<0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor—donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation.

Basal acetylcholine release in leech ganglia depolarizes neurons through receptors with a nicotinic binding site

1998 ◽  
Vol 201 (12) ◽  
pp. 1907-1915
Author(s):  
AM Burgin ◽  
L Szczupak
Keyword(s):  
Membrane Potential ◽  
Ache Activity ◽  
Acetylcholine Release ◽  
Ach Release ◽  
Cholinergic Agonists ◽  
Ache Inhibitors ◽  
Bath Application ◽  
Basal Release ◽  
Extracellular Level ◽  
Dose Dependent

The response of Retzius neurons, the main neuronal source of serotonin in the leech nervous system, to cholinergic agonists has been extensively investigated. In this study, we analyzed the effects of inhibiting the acetylcholinesterase (AChE) activity in the leech midbody ganglion on the electrophysiological activity of the Retzius neurons. Bath application of neostigmine and physostigmine (0.1-100 &mgr;mol l-1) produced, after a delay, a strong depolarization of the Retzius neurons with a dose-dependent amplitude and latency. The amplitude of this depolarization increased as the extracellular level of Ca2+ increased and decreased as the extracellular level of Ca2+ decreased. The response to neostigmine and physostigmine was inhibited by curare (100 &mgr;mol l-1), nicotine (10 &mgr;mol l-1), atropine (100 &mgr;mol l-1) and strychnine (100 &mgr;mol l-1), but was not affected by mecamylamine (100 &mgr;mol l-1) or hexamethonium (100 &mgr;mol l-1). Superfusion with solutions containing 100 &mgr;mol l-1 strychnine or atropine produced a progressive hyperpolarization of the Retzius neurons, while superfusion with 100 &mgr;mol l-1 curare did not. The hyperpolarization induced by atropine was inhibited in the presence of curare. Other neurons in the ganglion showed distinctive responses to the AChE inhibitors that were coincident with their responses to cholinergic agonists. The results suggest the existence of a basal level of acetylcholine (ACh) release in the leech ganglion that is powerfully counteracted by endogenous AChE activity. Under control conditions, this basal release appears to be sufficient to generate an ACh tonus that regulates the membrane potential of Retzius neurons. Since these neurons can support a sustained firing rate, which is dependent on the membrane potential, the results presented in this report suggest that the basal ACh tonus regulates the output of these neuromodulatory serotonergic neurons.

Revealing the mechanistic pathway of cholinergic inhibition of Alzheimer's disease by donepezil: a metadynamics simulation study

2019 ◽  
Vol 21 (25) ◽  
pp. 13578-13589 ◽  
Author(s):  
Shibaji Ghosh ◽  
Kalyanashis Jana ◽  
Bishwajit Ganguly
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Simulation Study ◽  
Acetylcholinesterase Inhibitor ◽  
Symptomatic Treatment ◽  
Mechanistic Pathway

Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the symptomatic treatment of Alzheimer's disease (AD).

scholarly journals Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3341
Author(s):  
Georgi Stavrakov ◽  
Irena Philipova ◽  
Atanas Lukarski ◽  
Mariyana Atanasova ◽  
Dimitrina Zheleva ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Ache Activity ◽  
Combinatorial Library ◽  
Acetylcholinesterase Inhibitors ◽  
Aβ Oligomers ◽  
Ache Inhibitors ◽  
Adme Properties ◽  
Dual Site ◽  
Site Binding

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer’s disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

2013 ◽  
Vol 765-767 ◽  
pp. 256-260
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Glycogen Synthase ◽  
Chinese Herbs ◽  
Multiple Targets ◽  
Active Compounds ◽  
Ache Inhibitors ◽  
Gsk 3Β ◽  
Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

Sign in / Sign up

Export Citation Format

Share Document