Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase: A computational and statistical analysis

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimer's disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcal/mol and -7.09kcal/mol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease.

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Ajmalicine and its Analogues Against AChE and BuChE for the Management of Alzheimer’s Disease: An In-silico Study

Current Pharmaceutical Design ◽

10.2174/1381612826666200407161842 ◽

2020 ◽

Vol 26 (37) ◽

pp. 4808-4814

Author(s):

Shu Liu ◽

Minyan Dang ◽

Yan Lei ◽

Syed S. Ahmad ◽

Mohammad Khalid ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Energy ◽

3D Structure ◽

Docking Studies ◽

Kcal Mole ◽

In Silico Study ◽

Phytochemical Compounds ◽

Inhibitory Potential ◽

Potential Inhibitors

Background: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions. Objective: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. Methods: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using ‘Autodock4.2’. Results: wo phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. Conclusion: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

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2',6'-dihydroxy-4'-methoxy dihydrochalcone improves the cognitive impairment of Alzheimer's disease: a structure-activity relationship study

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210701114034 ◽

2021 ◽

Vol 21 ◽

Author(s):

Ana E. Gonçalves ◽

Ângela Malheiros ◽

Camila A. Cazarin ◽

Lara de França ◽

David L. Palomino-Salcedo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Acetylcholinesterase Inhibitors ◽

Inhibitory Avoidance ◽

Symptomatic Treatment ◽

Memory Test ◽

Object Recognition Test ◽

Docking Simulations ◽

The Brain

Background: Chalcones and dihydrochalcones present potent inhibition of acetylcholinesterase, which is currently considered the most efficient approach for symptomatic treatment of Alzheimer’s disease. Objective: The present study aimed to explore the potential benefits of 2',6'-dihydroxy-4'-methoxy dihydrochalcone on the cognitive deficits of animals submitted to the streptozotocin-induced Alzheimer's model, as well as to evaluate the possible mechanisms of action. Methods: Learning and memory functions of different groups of animals were submitted to the streptozotocin-induced Alzheimer's model (STZ 2.5 mg/mL, i.c.v.) and subsequently treated with 2',6'-dihydroxy-4'-methoxy dihydrochalcone (DHMDC) administered at doses 5, 15, and 30 mg/kg (p.o.), rivastigmine (0,6 mg/kg, i.p.) and vehicle were evaluated in aversive memory test (inhibitory avoidance test) and spatial memory test (object recognition test). Molecular docking simulations were performed to predict the binding mode of DHMDC at the peripheral site of AChE to analyze noncovalent enzyme-ligand interactions. DFT calculations were carried out to study well-known acetylcholinesterase inhibitors and DHMDC. Results: DHMDC markedly increased the learning and memory of mice. STZ caused a significant decline of spatial and aversive memories in mice, attenuated by DHMDC (15 and 30 mg/kg). Furthermore, STZ conspicuously increased lipid peroxidation and compromised the antioxidant levels in mice brains. DHMDC pretreatment significantly increased GSH activity and other oxidative stress markers and decreased TBARS levels in the brain of STZ administered mice. AChE activity was significantly decreased by DHMDC in the brain of mice. Conclusion: The results together point that DHMDC may be a useful drug in the management of dementia.

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Multi-target Natural and Nature-Inspired Compounds against Neurodegeneration: A Focus on Dual Cholinesterase and Phosphodiesterase Inhibitors

Applied Sciences ◽

10.3390/app11115044 ◽

2021 ◽

Vol 11 (11) ◽

pp. 5044

Author(s):

Giovanni Ribaudo ◽

Maurizio Memo ◽

Alessandra Gianoncelli

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phosphodiesterase Inhibitors ◽

Acetylcholinesterase Inhibitors ◽

Symptomatic Treatment ◽

Brain Regions ◽

Complex Nature ◽

Promising Alternative ◽

Biochemical Mechanisms ◽

Underlying Mechanisms

Alzheimer’s disease is a memory-related neurodegenerative condition leading to cognitive impairment. Cholinergic deficit, together with other underlying mechanisms, leads the to onset and progression of the disease. Consequently, acetylcholinesterase inhibitors are used for the symptomatic treatment of dementia, even if limited efficacy is observed. More recently, some specific phosphodiesterase isoforms emerged as promising, alternative targets for developing inhibitors to contrast neurodegeneration. Phosphodiesterase isoforms 4,5 and 9 were found to be expressed in brain regions that are relevant for cognition. Given the complex nature of Alzheimer’s disease and the combination of involved biochemical mechanisms, the development of polypharmacological agents acting on more than one pathway is desirable. This review provides an overview of recent reports focused on natural and Nature-inspired small molecules, or plant extracts, acting as dual cholinesterase and phosphodiesterase inhibitors. In the context of the multi-target directed ligand approach, such molecules would pave the way for the development of novel agents against neurodegeneration. More precisely, according to the literature data, xanthines, other alkaloids, flavonoids, coumarins and polyphenolic acids represent promising scaffolds for future optimization.

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Molecular modeling and docking calculations of 4-acyloxy-biphenyl-4′-N-butylcarbamates as potential inhibitors of human butyrylcholinesterase

Canadian Journal of Chemistry ◽

10.1139/cjc-2015-0414 ◽

2016 ◽

Vol 94 (1) ◽

pp. 72-77 ◽

Cited By ~ 2

Author(s):

Yu-Fang Shen ◽

Gan-Hong Chen ◽

Shu-Hsien Lin ◽

Gialih Lin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Energy ◽

Linear Correlation ◽

Kinetic Studies ◽

Docking Studies ◽

Binding Energies ◽

Binding Modes ◽

Docking Calculations ◽

Potential Inhibitors

The kinetic studies and drug designs of butyrylcholinesterase play an important role in the development of Alzheimer’s disease therapeutics. In this research, automated docking studies were performed to provide useful insights into butyrylcholinesterase inhibition binding modes with designed 4-acyloxy-biphenyl-4′-N-butylcarbamates (compounds 1–8). Moreover, several significant linear correlations between experimental and calculated docking results are observed. Among compounds 1–7, compound 3, which exhibits the strongest hydrophobicity and has four carbonyl hydrogen bindings, shows the highest binding affinity (Ki = 1.4 μmol/L) with a binding energy of −7.99 kcal/mol. The observed linear correlation of experimental and calculated inhibition constants (Ki) indicates that the molecular docking results are reliable. Moreover, a good linear correlation is observed between calculated binding energies and experimental pKi. The experimental Hansch hydrophobicity constants (π values) are also correlated with the docked binding energy. This study reveals important correlations between butyrylcholinesterase experimental and docking results that contribute to the kinetic based identification of antagonists for the treatment of Alzheimer’s disease. Furthermore, these docked models provide important insights into a potential series of 4,4′-biphenol-based inhibitors of butyrylcholinesterase.

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Molecular Docking Studies, Bioactivity Score Prediction, Drug Likeness Analysis of GSK-3 β Inhibitors: A Target Protein Involved in Alzheimer’s Disease

Biosciences Biotechnology Research Asia ◽

10.13005/bbra/2650 ◽

2018 ◽

Vol 15 (2) ◽

pp. 455-467 ◽

Cited By ~ 3

Author(s):

Akanksha Joshi ◽

Rajesh Kumar ◽

Archit Sharma

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Targets ◽

Glycogen Synthase ◽

Acetylcholinesterase Inhibitors ◽

Docking Studies ◽

Binding Affinities ◽

Withanolide A ◽

Potent Drug ◽

Reliable Marker

Glycogen synthase kinase 3 β (GSK-3 Beta) is a potential target for developing an effective therapeutic effect in Alzheimer's disease (AD). Currently, no such drug or molecules has been found till date which can cure AD completely. Few drugs such as acetylcholinesterase inhibitors and memantine are ineffective in the later stages of the disease. Therefore, with the advancements in computational biology approaches, it is possible to combat alzheimer’s disease by targeting one of the kinases i.e. GSK-3 β involved in hyper phosphorylation of tau (a reliable marker of neurodegenerative disorders). In this study, we have carried out alzheimer’s structure-based drug designing with GSK-3 β. By applying appropriate docking methodology, we have identified few plant-derived compounds which show enhanced target selectivity than the conventional alzheimer's drug (such as memantine). Here we enumerate the comparison among the current and future AD therapy on the basis of their binding affinities. As a result, a large library of compounds has been screened as potent drug targets. It was also observed that withanolide–A (extracted from roots of withania somnifera) has the potential to emerge as the eventual drug for the AD. Moreover, few other phytocompounds such as celastrol, kenpaullone, quercetin, alsterpaullone have also shown enhanced activity in the decreasing order of their binding affinities.

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New Acetylcholinesterase Inhibitors for Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.1155/2012/728983 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 94

Author(s):

Mona Mehta ◽

Abdu Adem ◽

Marwan Sabbagh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Target ◽

Cholinesterase Inhibitors ◽

Treatment Approach ◽

Acetylcholinesterase Inhibitors ◽

Symptomatic Treatment ◽

Symptomatic Improvement ◽

Ache Inhibition ◽

Different Types

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

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Potent Acetylcholinesterase Inhibitors: Potential Drugs for Alzheimer’s Disease

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200103100521 ◽

2020 ◽

Vol 20 (8) ◽

pp. 703-715 ◽

Cited By ~ 10

Author(s):

Hulya Akıncıoğlu ◽

İlhami Gülçin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Free Radical ◽

Acetylcholinesterase Inhibitors ◽

Symptomatic Treatment ◽

Work Related ◽

Β Amyloid ◽

Hydrolysis Of ◽

Neurotransmitter Substance

: Alzheimer’s disease (AD) is one of the cognitive or memory-related impairments occurring with advancing age. Since its exact mechanism is not known, the full therapy has still not been found. Acetylcholinesterase (AChE) has been reported to be a viable therapeutic target for the treatment of AD and other dementias. To this end, acetylcholinesterase inhibitors (AChEIs) are commonly used. AChE is a member of the hydrolase enzyme family. A hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. AChE is useful for the development of novel and mechanism-based inhibitors. It has a role in the breakdown of acetylcholine (ACh) neurotransmitters, such as acetylcholinemediated neurotransmission. AChEIs are the most effective approaches to treat AD. AChE hydrolyzes ACh to acetate and choline, as an important neurotransmitter substance. Recently, Gülçin and his group explored new AChEIs. The most suggested mechanism for AD is the deficiency of ACh, which is an important neurotransmitter. In this regard, AChEIs are commonly used for the symptomatic treatment of AD. They act in different ways, such as by inhibiting AChE, protecting cells from free radical toxicity and β-amyloid-induced injury or inhibiting the release of cytokines from microglia and monocytes. This review focuses on the role of AChEIs in AD using commonly available drugs. Also, the aim of this review is to research and discuss the role of AChEIs in AD using commonly available drugs. Therefore, in our review, related topics like AD and AChEIs are highlighted. Also, the latest work related to AChEIs is compiled. In recent research studies, novel natural and synthetic AChEIs, used for AD, are quite noteworthy. These studies can be very promising in detecting potent drugs against AD.

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