scholarly journals Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease

2019 ◽  
Vol 20 (4) ◽  
pp. 1000 ◽  
Author(s):  
Minky Son ◽  
Chanin Park ◽  
Shailima Rampogu ◽  
Amir Zeb ◽  
Keun Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Active Site ◽  
Neurodegenerative Disorder ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Huperzine A ◽  
Potential Candidate ◽  
Binding Modes ◽  
Ache Inhibitors

Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive function. Since the previously approved AChE inhibitors, donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), have side effects and several studies are being carried out out to develop novel AD drugs, we have applied a three-dimensional quantitative structure−activity relationship (3D QSAR) and structure-based pharmacophore modeling methodologies to identify potential candidate inhibitors against AChE. Herein, 3D QSAR and structure-based pharmacophore models were built from known inhibitors and crystal structures of human AChE in complex with donepezil, galantamine, huperzine A, and huprine W, respectively. The generated models were used as 3D queries to screen new scaffolds from various chemical databases. The hit compounds obtained from the virtual screening were subjected to an assessment of drug-like properties, followed by molecular docking. The final hit compounds were selected based on binding modes and molecular interactions in the active site of the enzyme. Furthermore, molecular dynamics simulations for AChE in complex with the final hits were performed to evaluate that they maintained stable interactions with the active site residues. The binding free energies of the final hits were also calculated using molecular mechanics/Poisson-Boltzmann surface area method. Taken together, we proposed that these hits can be promising candidates for anti-AD drugs.

A Systematic Review on Donepezil-based Derivatives as Potential Cholinesterase Inhibitors for Alzheimer’s Disease

2019 ◽  
Vol 26 (30) ◽  
pp. 5625-5648 ◽  
Author(s):  
Jan Korabecny ◽  
Katarina Spilovska ◽  
Eva Mezeiova ◽  
Ondrej Benek ◽  
Radomir Juza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Nmda Receptor Antagonist ◽  
Amyloid Burden ◽  
Ache Inhibitors ◽  
Intellectual Capacity ◽  
Β Amyloid

: Alzheimer’s Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

2D- and 3D-QSAR Modeling of Imidazole-Based Glutaminyl Cyclase Inhibitors

2019 ◽  
Vol 15 ◽  
Author(s):  
Omar Husham Ahmed Al-Attraqchi ◽  
Katharigatta N. Venugopala
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Neurodegenerative Disorder ◽  
3D Qsar ◽  
Biological Evaluation ◽  
Qsar Modeling ◽  
Glutaminyl Cyclase ◽  
Validation Parameters ◽  
Qsar Models

Background: Glutaminyl cyclase (QC) is a novel target in the battle against Alzheimer’s disease, a highly prevalent neurodegenerative disorder. QC inhibitors have the potential to be developed as therapeutically useful anti-Alzheimer’s disease agents. Methods: Linear and non-linear 2D-quantitative structure–activity relationship (QSAR) models were developed using stepwise-multiple linear regression (S-MLR) and neural networks. Partial least squares (PLS) method was used to develop a 3D-QSAR model. Also, the developed models were used in a virtual screening of the ZINC database to identify potential QC inhibitors. Results: The 2D neural network model showed superior predictive ability, as demonstrated by the validation parameters R2 = 0.933, Q2 = 0.886 and R2pred = 0.911. The 3D-QSAR model’s steric and electrostatic fields’ isocontour maps were visualized and revealed important structural requirements associated with good activity. The virtual screening identified six compounds as potentially active QC inhibitors with improved pharmacokinetic profiles. Conclusion: The developed QSAR models can be used to predict the activity of compounds not yet synthesized and prioritize their synthesis and biological evaluation. Also, potentially active QC inhibitors have been identified with attractive lead-like properties that can be used to develop anti-Alzheimer’s disease agents.

The Efficacy and Safety of Alzheimer’s Disease Therapies: An Updated Umbrella Review

2021 ◽  
pp. 1-10
Author(s):  
Fangcheng Fan ◽  
Hua Liu ◽  
Xiaojie Shi ◽  
Yangwen Ai ◽  
Qingshan Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Activities Of Daily Living ◽  
Ginkgo Biloba ◽  
Daily Living ◽  
Huperzine A ◽  
Cochrane Library ◽  
Efficacy And Safety ◽  
Umbrella Review ◽  
Ache Inhibitors

Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer’s disease (AD) are sparse. Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. Results: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

scholarly journals In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 54-68 ◽  
Author(s):  
Kanzal Iman ◽  
Muhammad Usman Mirza ◽  
Nauman Mazhar ◽  
Michiel Vanmeert ◽  
Imran Irshad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
In Silico Analysis ◽  
Acetylcholinesterase Inhibitors ◽  
Binding Energies ◽  
Therapeutic Interventions ◽  
Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

scholarly journals AchE-OGT dual inhibitors: Potential Partners in Handling Alzheimer’s Disease

2018 ◽  
Author(s):  
Mukta Sharma ◽  
Ashwin K. Jainarayanan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Active Site ◽  
Neurodegenerative Disorder ◽  
3D Structure ◽  
Pharmacophore Model ◽  
Structural Features ◽  
Ache Inhibitor ◽  
Dual Inhibitors

AbstractThe emerging role of O-GlcNAc Transferase (OGT) and tau protein in Alzheimer’s disease (AD) holds promises for the treatment of this life-threatening neurodegenerative disorder. In view of the availability of 3D structure of OGT, we attempted to develop structure-based pharmacophore model to elucidate specific structural requirements for binding of inhibitors to the active site of OGT. During the course of study we discovered that donepezil, an old and trusted Acetylcholinesterase (AchE) inhibitor also possess the pharmacophoric sites important for interaction with OGT active site. To further explore the specific interactions of donepezil with OGT, we performed molecular docking studies using CDocker. The results of molecular docking and structure-based pharmacophore mapping revealed that donepezil has the required structural features to interact with various OGT active site amino acids like Lys842, His920, Leu653, Gly654, Asn838, and Thr921 in addition to its AchE interaction abilities. Our findings could be an important breakthrough in the design of OGT specific and/or AchE OGT dual inhibitors.

scholarly journals Potential Therapeutic Approaches to Alzheimer’s Disease By Bioinformatics, Cheminformatics And Predicted Adme-Tox Tools

2020 ◽  
Vol 18 (8) ◽  
pp. 696-719
Author(s):  
Speranta Avram ◽  
Maria Mernea ◽  
Carmen Limban ◽  
Florin Borcan ◽  
Carmen Chifiriuc
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptors ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
Natural Compounds ◽  
Synthetic Compounds ◽  
Ache Inhibitors

Background: Alzheimer’s disease (AD) is considered a severe, irreversible and progressive neurodegenerative disorder. Currently, the pharmacological management of AD is based on a few clinically approved acethylcholinesterase (AChE) and N-methyl-D-aspartate (NMDA) receptor ligands, with unclear molecular mechanisms and severe side effects. Methods: Here, we reviewed the most recent bioinformatics, cheminformatics (SAR, drug design, molecular docking, friendly databases, ADME-Tox) and experimental data on relevant structurebiological activity relationships and molecular mechanisms of some natural and synthetic compounds with possible anti-AD effects (inhibitors of AChE, NMDA receptors, beta-secretase, amyloid beta (Aβ), redox metals) or acting on multiple AD targets at once. We considered: (i) in silico supported by experimental studies regarding the pharmacological potential of natural compounds as resveratrol, natural alkaloids, flavonoids isolated from various plants and donepezil, galantamine, rivastagmine and memantine derivatives, (ii) the most important pharmacokinetic descriptors of natural compounds in comparison with donepezil, memantine and galantamine. Results: In silico and experimental methods applied to synthetic compounds led to the identification of new AChE inhibitors, NMDA antagonists, multipotent hybrids targeting different AD processes and metal-organic compounds acting as Aβ inhibitors. Natural compounds appear as multipotent agents, acting on several AD pathways: cholinesterases, NMDA receptors, secretases or Aβ, but their efficiency in vivo and their correct dosage should be determined. Conclusion: Bioinformatics, cheminformatics and ADME-Tox methods can be very helpful in the quest for an effective anti-AD treatment, allowing the identification of novel drugs, enhancing the druggability of molecular targets and providing a deeper understanding of AD pathological mechanisms.

scholarly journals Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

2021 ◽  
Author(s):  
Zhenquan Xuan ◽  
Xingmei Gu ◽  
Sicheng Yan ◽  
Yanfei Xie ◽  
Yiying Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurotrophic Factor ◽  
Neurodegenerative Disorder ◽  
Brain Derived Neurotrophic Factor ◽  
Huperzine A ◽  
Bdnf Expression ◽  
Neuroprotective Effects ◽  
Aβ Oligomers

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, multi-target-directed ligands (MTDLs) strategy has been developed to combat this disease. We have previously designed and synthesized dimeric tacrine (10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognition-enhancing ability in AD animal models. Methods Behavioral and biochemical methods were applied to evaluate multi-target cognitive-enhancing effects and mechanisms of A10E in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice. The neuroprotective mechanisms of A10E were explored in SH-SY5Y cells. And the anti-aggregation effects of A10E on Aβ were directly investigated in vitro. Results A10E could prevent cognitive impairments in both APP/PS1 mice and Aβ oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, reduce neuroinflammation, enhance brain derived brain-derived neurotrophic factor (BDNF) expression, and elevate cholinergic neurotransmission in vivo. A10E, at nanomolar concentrations, could also inhibit Aβ oligomers-induced neurotoxicity via the activation of the TrkB/Akt pathway. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Conclusion A10E could produce anti-AD neuroprotective effects via multi-target mechanisms, including the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the reduction of neuroinflammation and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

Auditory Dysfunction in Alzheimer's Disease

2010 ◽  
Vol 15 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Sridhar Krishnamurti
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Health Care ◽  
Care Setting ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Clinical Protocols ◽  
Speech Language Pathologist ◽  
Auditory Dysfunction

Alzheimer's disease is neurodegenerative disorder which affects a growing number of older adults every year. With an understanding of auditory dysfunction in Alzheimer's disease, the speech-language pathologist working in the health care setting can provide better service to these individuals. The pathophysiology of the disease process in Alzheimer's disease increases the likelihood of specific types of auditory deficits as opposed to others. This article will discuss the auditory deficits in Alzheimer's disease, their implications, and the value of clinical protocols for individuals with this disease.

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

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