scholarly journals Synthesis and DPPH scavenging assay of reserpine analogues, computational studies and in silico docking studies in AChE and BChE responsible for Alzheimer's disease

2015 ◽  
Vol 51 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Muhammad Yar ◽  
Muhammad Arshad ◽  
Ariba Farooq ◽  
Mazhar Amjad Gilani ◽  
Khurshid Ayub ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
In Silico ◽  
Density Functional ◽  
Neurodegenerative Disorder ◽  
Antioxidant Properties ◽  
Docking Studies ◽  
In Silico Docking ◽  
Ic50 Values

Alzheimer's disease (AD) is a fast growing neurodegenerative disorder of the central nervous system and anti-oxidants can be used to help suppress the oxidative stress caused by the free radicals that are responsible for AD. A series of selected synthetic indole derivatives were biologically evaluated to identify potent new antioxidants. Most of the evaluated compounds showed significant to modest antioxidant properties (IC50 value 399.07 140.0±50 µM). Density Functional Theory (DFT) studies were carried out on the compounds and their corresponding free radicals. Differences in the energy of the parent compounds and their corresponding free radicals provided a good justification for the trend found in their IC50 values. In silico, docking of compounds into the proteins acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are well known for contributing in AD disease, was also performed to predict anti-AD potential.

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.

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 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.

Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine

2020 ◽  
Vol 16 (7) ◽  
pp. 947-957
Author(s):  
Maja Przybyłowska ◽  
Iwona Inkielewicz-Stepniak ◽  
Szymon Kowalski ◽  
Krystyna Dzierzbicka ◽  
Sebastian Demkowicz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sodium Iodide ◽  
31P Nmr ◽  
Neurodegenerative Disorder ◽  
Docking Studies ◽  
New Drugs ◽  
Binding Ability ◽  
Electric Eel ◽  
Cholinesterase Inhibitory Activity

Background: Alzheimer’s disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. Objective: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer’s disease (AD) agents. Methods: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. Results: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. Conclusion: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).

scholarly journals Synthesis of Coumarins Linked With 1,2,3-Triazoles under Microwave Irradiation and Evaluation of their Antimicrobial and Antioxidant Activity

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Nibin Joy Muthipeedika ◽  
Yadav D Bodke ◽  
Sandeep Telkar ◽  
Vasily A Bakulev
Keyword(s):  
Antioxidant Activity ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Antioxidant Properties ◽  
Cycloaddition Reaction ◽  
Antibacterial Activities ◽  
Docking Studies ◽  
In Silico Docking ◽  
Antimicrobial And Antioxidant Activity ◽  
Plausible Reason

A series of coumarin derivatives linked with 1,2,3-triazoles has been synthesized by utilizing the copper catalyzed azide-alkyne cycloaddition reaction and were screened for their antimicrobial and antioxidant properties. Some of the compounds displayed promising antibacterial activities (MIC ranging from 5-150 µg/mL) and moderate antifungal activities as compared to the respective standards. The compounds 4k and 4g displayed good antibacterial activity when compared with the standard, Ciprofloxacin, and 4n exhibited better antifungal activity when compared to other synthesized compounds. The in silico docking studies of the active compounds were carried out against the gyrase enzyme and from those studies, it was acknowledged that 4k possessed significant hydrogen bonding and hydrophobic interactions which could be the plausible reason for its superior activity as compared to the other synthesized compounds. The compounds 4h and 4q showed promising antioxidant activity when compared with the standard, BHT, which could be attributed to the presence of electron donating substituents.                                                Resumen. Una serie de derivados de cumarina enlazados con 1,2,3-triazoles fue sintetizada empleando la reacción de cicloadición azida-alquino catalizada con cobre y fue evaluada en sus propiedades antimicrobianas y antioxidantes. Algunos de los compuestos exhibieron actividad antimicrobiana promisoria (intervalo MIC de 5-150 µg/mL) y actividad antifúngica moderada con respecto a los estándares respectivos. Los compuestos 4g y 4k mostraron buena actividad antibacterial con relación al estándar. Fluconazole y 4n exhibieron mejor actividad antifúngica en comparación con el resto de los compuestos. Se llevaron a cabo estudios in silico de modelado molecular e interacción de los compuestos activos con la enzima girasa ADN. De estos estudios se observó que 4k posee enlaces puentes de hidrógeno e interacciones hidrofóbicas significativos, los cuales podrían ser una causa plausible de su actividad mayor a aquélla mostrada por los otros compuestos sintetizados. Los compuestos 4h y 4q mostraron una importante actividad antioxidante comparada con el estándar (BHT), lo cual podría atribuirse a la presencia de sustituyentes electro-donadores

Multi-Target-Directed Ligands Affecting Serotonergic Neurotransmission for Alzheimer’s Disease Therapy: Advances in Chemical and Biological Research

2018 ◽  
Vol 25 (17) ◽  
pp. 2045-2067 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Anna Wesolowska ◽  
Maciej Pawlowski ◽  
Grazyna Chlon-Rzepa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Intracellular Signaling ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Bipolar Depression ◽  
Antioxidant Properties ◽  
Biological Research ◽  
Serotonergic Neurotransmission ◽  
Age Related

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and chronic inflammation that affects over 30 million people all over the world. Most of the Alzheimer's patients also suffer from psychosis, aggression, agitation, depression, anxiety, and many other behavioral and psychological symptoms of dementia. Unfortunately, the currently available anti-AD drugs provide modest symptomatic relief, and they do not reverse the neurodegeneration. Therefore, the average life expectancy after diagnosis is between six and ten years. Research data suggest that multi-target-directed ligands (MTDLs) give an opportunity to prevent, halt, or reverse the progression of AD, and reduce the symptoms of the disease. The aim of this review is to update the most recent reports on the development of MTDLs affecting serotonergic neurotransmission as potential drugs for both symptomatic and disease-modifying therapy of AD. Multifunctional modulators of serotonergic system exerted procognitive, antipsychotic, antidepressant, and/or anxiolytic properties in preclinical studies. Some of them revealed their potential as modulators of tau phosphorylation or amyloid beta aggregation with neuroprotective, anti-inflammatory, and/or antioxidant properties. Among them, lumateperone - an inhibitor of serotonin transporter with a high affinity for serotonergic and dopaminergic receptors is currently being tested in clinical trials in patients with dementia, bipolar depression, or schizophrenia. The high therapeutic potential of MTDLs as anti-AD drugs seems to be the result of their involvement in multiple neurotransmitter systems and intracellular signaling pathways.

Indane-1,3-diones: as potential and selective α-glucosidase inhibitors, their synthesis, in vitro and in silico studies.

2020 ◽  
Vol 16 ◽  
Author(s):  
Asma Mukhtar ◽  
Shazia Shah ◽  
Kanwal ◽  
Shehryar Hameed ◽  
Khalid Mohammed Khan ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Docking Studies ◽  
Moderate Activity ◽  
Spectroscopic Techniques ◽  
In Silico Docking ◽  
In Silico Studies ◽  
Synthetic Molecules ◽  
Ic50 Values

Background: Diabetes mellitus is one the most chronic metabolic disorder. Since past few years our research group had synthesized and evaluated libraries of heterocyclic compounds against α and β-glucosidase enzymes and found encouraging results. The current study comprises of evaluation of indane-1,3-dione as antidiabetic agents based on our previously reported results obtained from closely related moiety isatin and its derivatives. Objective: A library of twenty three indane-1,3-dione derivatives (1-23) was synthesized and evaluated for α and βglucosidase inhibitions. Moreover, in silico docking studies were carried out to investigate the putative binding mode of selected compounds with the target enzyme. Method: The indane-1,3-dione derivatives (1-23) were synthesized by Knoevenagel condensation of different substituted benzaldehydes with indane-1,3-dione under basic condition. The structures of synthetic molecules were deduced by using different spectroscopic techniques including 1H-, 13C-NMR, EI-MS, and CHN analysis. Compounds (1-23) were evaluated for α and β-glucosidase inhibitions by adopting the literature protocols. Result: Off twenty three, eleven compounds displayed good to moderate activity against α-glucosidase enzyme, nonetheless, all compounds exhibited less than 50% inhibition against β-glucosidase enzyme. Compounds 1, 14, and 23 displayed good activity against α-glucosidase enzyme with IC50 values of 2.80 ± 0.11, 0.76 ± 0.01, and 2.17 ± 0.18 µM, respectively. The results have shown that these compounds have selectively inhibited the α-glucosidase enzyme. The in silico docking studies also supported the above results and showed different types of interactions of synthetic molecules with the active site of enzyme. Conclusion: The compounds 1, 14, and 23 have shown good inhibition against α-glucosidase and may potentially serve as lead for the development of new therapeutic representatives.

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.

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