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 In-vitro AND In-silico CORRELATION STUDIES OF NATURAL AChE INHIBITORS: AN APPROACH TOWARDS ALZHEIMER’S DISEASE

2021 ◽  
pp. 83-91
Author(s):  
Vasudev Pai ◽  
K. S. Chandrashekar ◽  
Aravind Pai ◽  
Anuraag Muralidharan ◽  
M. Manjunath Setty
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Correlation Studies ◽  
Ache Inhibitors

scholarly journals Essential Oil of Lippia origanoides H.B.K.: A Promising Compound Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

2021 ◽  
Author(s):  
Aldenora Maria Ximenes Rodrigues ◽  
Brenda Nayranne Gomes dos Santos ◽  
Ranyelison Silva Machado ◽  
Rubens Renato de Sousa Carmo ◽  
Matheus Pedrosa de Oliveira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
In Silico ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
New Drugs ◽  
Gas Chromatography Mass Spectrometry ◽  
Low Toxicity

Alzheimer's disease is characterized by a progressive decline of cognitive functions. The class of drugs used for the treatment are acetylcholinesterase inhibitors. Essential oils have contributed to folk medicine and discovery of new drugs for a long time. The purpose of the study was to investigate the in vitro and in silico the anti-acetylcholinesterase activity, as well as acute toxicity of the essential oil of Lippia origanoides. EOLO was obtained by hydrostelting and analyzed by gas chromatography-mass spectrometry. The inhibition assay of acetylcholinesterase enzyme activity was evaluated in vitro, as well as in silico by docking. The effects of EOLO on hematological, biochemical and behavioral parameters were analyzed in mices. We expose that EOLO shows good anti-acetylcholinesterase activity and low toxicity, possibly resulting from the action of the majority compounds thymol, carvacrol and p-cymene. The anti-acetylcholinesterase potential in vitro demonstrating a 70% inhibition. The docking results elucidated the participation of the major phenolics in AChE inhibition by interacting with the catalytic cavity of AchE. The acute oral toxicity test classified as low toxicity. These results contribute to expand the knowledge about essential oil of Lippia origanoides. Therefore, appears to be promising for herbal medicine production with anti-acetylcholinesterase and antioxidant activity.

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.

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.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

2020 ◽  
Vol 20 ◽  
Author(s):  
Dnyaneshwar Baswar ◽  
Abha Sharma ◽  
Awanish Mishra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Cholinergic Neurons ◽  
In Silico Screening ◽  
In Silico Studies ◽  
Bbb Permeability ◽  
Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

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