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 Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signaling, glucose scavenging and drug detoxification and are essential for parasite survival

2019 ◽  
Author(s):  
Bemnet Tedla ◽  
Javier Sotillo ◽  
Darren Pickering ◽  
Ramon M. Eichenberger ◽  
Luke Becker ◽  
...  
Keyword(s):  
Developmental Expression ◽  
Laboratory Animals ◽  
Parasite Development ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Cholinergic Signaling ◽  
Parasite Survival ◽  
Drug Detoxification

AbstractCholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 – smp_154600 and Smache3 – smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 – smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument and neuromusculature of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. To address the hypothesis that tegumental AChE mediates exogenous glucose scavenging by the parasite, we show that RNAi-mediated knockdown of smache1 and smache3, but not smbche1, significantly reduces glucose uptake by schistosomes. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor DDVP (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.Author summaryCholinesterases - aceytlcholinesterases (AChE)s and butyrylcholinesterases (BChE)s - are multi-functional enzymes that play a pivotal role in the nervous system of parasites by regulating neurotransmission through acetylcholine hydrolysis. Herein, we provide a detailed characterization of schistosome cholinesterases using molecular, enzymatic and gene-silencing approaches and show evidence for these molecules having roles in glucose scavenging and drug detoxification, in addition to their neuronal function. Further, we demonstrate the importance of these proteins to parasite development and survival through gene knockdown experiments in laboratory animals, providing evidence for the use of these proteins in the development of novel intervention strategies against schistosomiasis.

scholarly journals Slow-binding reversible inhibitor of acetylcholinesterase with long-lasting action for prophylaxis of organophosphate poisoning

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Oksana A. Lenina ◽  
Irina V. Zueva ◽  
Vladimir V. Zobov ◽  
Vyacheslav E. Semenov ◽  
Patrick Masson ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Ex Vivo ◽  
Health Hazard ◽  
Ache Inhibitor ◽  
Reversible Inhibitor ◽  
Organophosphate Poisoning ◽  
Exposure Treatment ◽  
Ache Inhibitors ◽  
Pre Treatment

Abstract Organophosphorus (OP) compounds represent a serious health hazard worldwide. The dominant mechanism of their action results from covalent inhibition of acetylcholinesterase (AChE). Standard therapy of acute OP poisoning is partially effective. However, prophylactic administration of reversible or pseudo-irreversible AChE inhibitors before OP exposure increases the efficiency of standard therapy. The purpose of the study was to test the duration of the protective effect of a slow-binding reversible AChE inhibitor (C547) in a mouse model against acute exposure to paraoxon (POX). It was shown that the rate of inhibition of AChE by POX in vitro after pre-inhibition with C547 was several times lower than without C547. Ex vivo pre-incubation of mouse diaphragm with C547 significantly prevented the POX-induced muscle weakness. Then it was shown that pre-treatment of mice with C547 at the dose of 0.01 mg/kg significantly increased survival after poisoning by 2xLD50 POX. The duration of the pre-treatment was effective up to 96 h, whereas currently used drug for pre-exposure treatment, pyridostigmine at a dose of 0.15 mg/kg was effective less than 24 h. Thus, long-lasting slow-binding reversible AChE inhibitors can be considered as new potential drugs to increase the duration of pre-exposure treatment of OP poisoning.

scholarly journals A Novel Galantamine-Curcumin Hybrid as a Potential Multi-Target Agent against Neurodegenerative Disorders

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1865
Author(s):  
Rumyana Simeonova ◽  
Dimitrina Zheleva ◽  
Iva Valkova ◽  
Georgi Stavrakov ◽  
Irena Philipova ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Neurodegenerative Disorders ◽  
Ex Vivo ◽  
Radical Scavenging ◽  
Toxicity Tests ◽  
Ache Inhibitor ◽  
In Vitro Tests ◽  
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) and in vitro DPPH, ABTS, FRAP and LPO inhibition assays. Hematological 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, as well as a 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The antioxidant activity of 4b measured ex vivo was proven in the in vitro tests. In the ABTS assay, 4b showed radical scavenging activity 10 times higher than the positive control butylhydroxy toluol (BHT). The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a prospective multitarget drug candidate for treatment of neurodegenerative disorders.

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 Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity

2020 ◽  
Author(s):  
Muhammad Usman Mirza ◽  
Sarfraz Ahmad ◽  
Iskandar Abdullah ◽  
Matheus Froeyen
Keyword(s):  
Virtual Screening ◽  
Critical Role ◽  
Md Simulations ◽  
Binding Mode ◽  
Catalytic Triad ◽  
Ic50 Value ◽  
Cell Assays ◽  
Screening Protocol ◽  
Specific Protease

The ubiquitin-specific protease 2 (USP) belongs to the family of deubiquitinases and plays a critical role in tumors cells’ survival and therefore signifies an important therapeutic target. Previous studies have indicated promising efficacies of potent human USP2 inhibitors including, thiopurine analogues against SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb–palm–fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated structure-based virtual screening efforts. After a subsequent virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 µM) and MOTL-4 cells (11.8 µM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.

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 ANTICHOLINESTERASE ACTIVITY OF OCTA PEPTIDES RELATED TO HUMAN HISTATIN 8: IN-SILICO DRUG DESIGN AND IN-VITRO

2017 ◽  
Vol 10 (6) ◽  
pp. 115 ◽  
Author(s):  
Pandurangan Perumal ◽  
Mani Vasudevan ◽  
Sridevi Chigurupati ◽  
Manikandan Selvaraj
Keyword(s):  
In Silico ◽  
Potent Inhibitor ◽  
Docking Study ◽  
Ache Inhibitor ◽  
In Silico Docking ◽  
In Silico Drug Design ◽  
Ic50 Value ◽  
Ache Inhibitory Activity ◽  
Histatin 8

Objective: To evaluate the octapeptides related to human histatin 8 by in-silico and in-vitro studies.Method: Schrodinger, LLC and Ellman’s method.Results: The compound HH1 and HH2 was found to be potent docking score of −9.494 and −7.401 against acetylcholinesterase (AChE) enzyme. The IC50 value of HH1 and HH2 was found to be 0.39±0.28 and 0.78±0.15 μg/mL. However, these compounds are shown to be highly effective as compared with the control AChE inhibitor donepezil (0.065±0.0050 μg/mL).Conclusion: In-silico docking study was conducted for the designed octapeptides related to human histatin 8 against AChE enzyme shows significance binding affinity toward HH1 and HH2 peptides and the AChE inhibitory activity of octapeptides shown to be a highly potent inhibitor as compared with control donepezil.

scholarly journals Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2536
Author(s):  
Cédric Lecoutey ◽  
Rémi Legay ◽  
Audrey Davis ◽  
Jana Sopková-de Oliveira Santos ◽  
Patrick Dallemagne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Stage ◽  
Receptor Agonist ◽  
Acetylcholinesterase Inhibitor ◽  
Structural Diversity ◽  
Docking Study ◽  
Disease Treatment ◽  
Ache Inhibitors

The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.

scholarly journals IN VITRO SCREENING FOR ACETYLCHOLINESTERASE ENZYME INHIBITION POTENTIAL OF MUTHU PARPAM – THERAPEUTIC LEAD FOR ALZHEIMER’S DISEASE

2020 ◽  
pp. 56-58
Author(s):  
SABARI GIRIJA N ◽  
GUPTAJ S ◽  
SINEKHA MA ◽  
SAKTHIMANIPRIYA L ◽  
SHANMUGAPRIYA P
Keyword(s):  
Positive Control ◽  
Ache Inhibitor ◽  
Ache Inhibition ◽  
Neurocognitive Dysfunction ◽  
Preliminary Screening ◽  
Traditional System ◽  
Maximum Inhibition ◽  
Acetylcholinesterase Enzyme ◽  
Ellman’S Method

Objective: Siddha system is an ancient traditional system of medicine treats many chronic ailments and neurological disorders. Muthu parpam is one of the herbo marine Siddha drugs which have the indication for neurocognitive dysfunction. The main objective of this current study was to evaluate the acetylcholine esterase (AChE) inhibition of Muthu parpam. Methods: AChE activity was evaluated using a modified 96-well microplate assay based on Ellman’s method. Physostigmine (5, 10, 20, and 40 μg/ml) was used as the positive control. Results: The result of this study clearly indicates that the test drug Muthu Parpam was effective in inhibiting AChE enzyme at the specified concentration dose dependently. Maximum percentage inhibition of about 71.68% was observed at 500 μg/ml when compared to that of the Physostigmine, a known AChE inhibitor with the maximum inhibition 84.87% at the concentration of 40 μg/ml. Conclusion: Hence, this preliminary screening has proven the efficacy of Muthu parpam through AChE inhibition potential in the management of Alzheimer disease.

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.

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