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

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.

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

2016 ◽  
Vol 94 (1) ◽  
pp. 72-77 ◽  
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.

scholarly journals MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER'S DISEASE (AChE AND BChE) USING NATURAL BIOACTIVE ALKALOIDS

2016 ◽  
Vol 8 (12) ◽  
pp. 108
Author(s):  
Punabaka Jyothi ◽  
Kuna Yellamma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Neurodegenerative Disorder ◽  
Biological Activities ◽  
Neuropsychiatric Symptoms ◽  
Docking Studies ◽  
Kcal Mole ◽  
Molecular Docking Studies

Objective: Alzheimer’s disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms, is biochemically characterized by a significant decrease in the brain neurotransmitter Acetylcholine (ACh).Methods: In the present insilico study, six plant bioactive compounds namely Harmol, Vasicine, Harmaline, Harmine, Harmane and Harmalol (from P. Nigellastrum Bunge) were analyzed for their inhibitory role on AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) activity by applying the molecular docking studies. Other parameters viz. determination of molecular interaction-based binding affinity values, protein-ligand interactions, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools.Results: The results of docking analysis clearly showed that Harmalol has highest binding affinity with AChE (-8.6 kcal/mole) and BChE (-8.0 kcal/mole) but it does not qualified the enzyme inhibitory activity, since it was exerted, and also has least percentage activity on AD and neurodegenerative disease. Whereas, the Harmine has been second qualified binding affinity (-8.4 kcal/mol) and first in other parameters when compared with Harmalol.Conclusion: Based on docking results and other parameters conducted, we are concluding that Harmine is the best compound for further studies to treat AD.Keywords: Alzheimer's disease (AD), Acetylcholinesterase, Butyrylcholinesterase, Lead Molecules

scholarly journals The Treatment of Alzheimer’s Disease through Molecular Docking Studies using Phyltetralin against Kallikrein_6: A Bioinformatic Approach

2021 ◽  
Vol 9 (VI) ◽  
pp. 3992-3999
Author(s):  
Sarita Negi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Binding Energy ◽  
In Silico ◽  
Receptor Protein ◽  
Mean Square ◽  
Mean Square Deviation ◽  
In Silico Study ◽  
Kallikrein 6

Alzheimer's disease (AD) is a neurodegenerative disease that generally begins leisurely and gets worse with time. Alzheimer’s disease (AD) dementia is the specific beginning of age-related declination of cognitive abilities and function, which eventually leads to death. Alzheimer’s disease (AD) is one of the neurodeteriorating disorders which is one of the mostcritical complications that our current health care system faces. The phenomenon of molecular docking has progressively become a strong tool in the field of pharmaceutical research including drug discovery. The aim of the presentin silico study was to inhibit the expression of KLK-6 (kallikrein-6) which is a target or receptor protein by its interaction with three distinct secondary metabolites for treating Alzheimer's disease (AD) through molecular docking. Methods: The in-silico study was based on molecular docking. Docking was executed amidst ligands- Quercetin (CID: 5280343), Ricinoleic Acid (CID: 643684), Phyltetralin (CID: 11223782), and the target or receptor protein Kallikrein-6 (PDB ID: 1LO6). The protein and the ligands were downloaded in the required format. Through PyRx, the ligands were virtually screened after importing them in the PyRx window. The results of PyRx and SwissADME were analyzed and the best ligand was finalized. Among the three, Phyltetralin was the best ligand contrary to KLK-6 having minimum binding energy and it was following Lipinski’s five rules along with 0 violations. Results: The final docking was carried out between Phyltetralin and KLK-6 through AutoDock Vina. The outcome showed 9 poses with distinct binding energy, RSMD LB (root mean square deviation lower bound) and RSMD UB (root mean square deviation upper bound). With the help of PyMOL which is an open-access tool for molecular visualization, the interaction amidst Phyltetralin and KLK-6 can be visualized. Conclusion: Based on this in silico study it can be concluded that KLK-6 (kallikrein-6) which is responsible for causing AD can be inhibited by ligand Phyltetralin and for the treatment of AD, phyltetralin might act as a potential drug. Thus, in future studies, Phyltetralin from natural sources can prevent Alzheimer's disease and can be proved as a promising and efficient drug for treating Alzheimer's disease.

scholarly journals Decoding Conformational Imprint of Convoluted Molecular Interactions Between Prenylflavonoids and Aggregated Amyloid-Beta42 Peptide Causing Alzheimer’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
E. Srinivasan ◽  
G. Chandrasekhar ◽  
P. Chandrasekar ◽  
K. Anbarasu ◽  
AS Vickram ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Fibril Structure ◽  
Potential Inhibitors

Protein misfolding occurs due to the loss of native protein structure and adopts an abnormal structure, wherein the misfolded proteins accumulate and form aggregates, which result in the formation of amyloid fibrils that are associated with neurodegenerative diseases. Amyloid beta (Aβ42) aggregation or amyloidosis is contemplated as a unique hallmark characteristic of Alzheimer’s disease (AD). Due to aberrant accrual and aggregation of Aβ42 in extracellular space, the formation of senile plaques is found in AD patients. These senile plaques occur usually in the cognitive and memory region of the brain, enfeebles neurodegeneration, hinders the signaling between synapse, and disrupts neuronal functioning. In recent years, herbal compounds are identified and characterized for their potential as Aβ42 inhibitors. Thus, understanding their structure and molecular mechanics can provide an incredible finding in AD therapeutics. To describe the structure-based molecular studies in the rational designing of drugs against amyloid fibrils, we examined various herbal compounds that belong to prenylflavonoids. The present study characterizes the trends we identified at molecular docking studies and dynamics simulation where we observed stronger binding orientation of bavachalcone, bavachin, and neobavaisoflavone with the amyloid-beta (Aβ42) fibril structure. Hence, we could postulate that these herbal compounds could be potential inhibitors of Aβ42 fibrils; these anti-aggregation agents need to be considered in treating AD.

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

2022 ◽  
Vol 67 (4) ◽  
pp. 106-114
Author(s):  
Syed Sayeed Ahmad ◽  
Haroon Khan ◽  
Mohammad Khalid ◽  
Abdulraheem SA Almalki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
Human Brain ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Docking Studies ◽  
Coefficient Of Determination ◽  
Intermolecular Energy ◽  
Brain Acetylcholinesterase

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.

Drug Design of Inhibitors of Alzheimer’s Disease (AD): POM and DFT Analyses of Cholinesterase Inhibitory Activity of β-amino di-Carbonyl Derivatives

2019 ◽  
Vol 19 (8) ◽  
pp. 688-705
Author(s):  
Taibi Ben Hadda ◽  
Abdur Rauf ◽  
Hsaine Zgou ◽  
Fatma Sezer Senol ◽  
Ilkay Erdogan Orhan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Metal Accumulation ◽  
Microtiter Plate ◽  
Metal Chelation ◽  
Carbonyl Derivatives ◽  
Cholinesterase Inhibitory Activity ◽  
Inhibitory Potential

Background:Since deficit of acetylcholine has been evidenced in the Alzheimer’s disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD.Method:In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 μg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity.Results and Conclusion:All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

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