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.

scholarly journals Design, synthesis and biological evaluation of substituted pyrazoles endowed with brominated 4-methyl 7-hydroxy coumarin as new scaffolds against Alzheimer’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Siju Ellickal Narayanan ◽  
Hariraj Narayanan ◽  
Minil Mukundan ◽  
Saranya Balan ◽  
C. P. Vishnupriya ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Property ◽  
Docking Studies ◽  
Acetylcholine Esterase ◽  
Coumarin Derivatives ◽  
Docking Score ◽  
Hydroxy Coumarin

Abstract Background The study aimed to design, synthesize and evaluate various brominated derivatives of 7-hydroxy coumarin as a new scaffold against Alzheimer’s disease by in vivo and in vitro models. A group of three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed. Among the designed compounds, a single entity (D1) was selected based on the docking score, which could be considered mainly for the treatment of Alzheimer’s disease. Three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed and docking studies of these compounds were carried out using Argus lab4.0.1 version. According to the docking score, a single entity of compound (D1) was selected for further study. The structure of the compound (D1) was explored by spectral analysis. The anti-Alzheimer’s activity was evaluated by in vivo and in vitro methods. All results were compared statistically by one-way ANOVA using GraphPad Prism. Results Molecular docking studies revealed that the compound D1 was able to bind simultaneously to the amino acid and in the active sites of the acetylcholine esterase enzyme. In acetylcholine esterase inhibition assay, the compound shows a significant increase in acetylcholine esterase level. The MAO inhibitory activities were in the nanomole range (human MAO-A IC50 = 3.9, human MAO-B IC 50 = 4.4). DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay showed that the compound shows a promising antioxidant property. In the evaluation of learning and memory of compound D1 using elevated plus maze, the compound D1-pretreated group showed a significant increase in memory and learning when compared with donepezil. Conclusions Among the designed series of pyrazole endowed with brominated 7-hydroxyl 4-methyl coumarin derivatives, compound D1 showed good antioxidant property and acetylcholine esterase and MAO inhibitory activity; based on this property, the synthesized compound D1 can be considered a new scaffold on Alzheimer’s disease.

scholarly journals Korean Thistle (Cirsium japonicum var. maackii (Maxim.) Matsum.): A Potential Dietary Supplement against Diabetes and Alzheimer’s Disease

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 649 ◽  
Author(s):  
Aditi Wagle ◽  
Su Hui Seong ◽  
Srijan Shrestha ◽  
Hyun Ah Jung ◽  
Jae Sue Choi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dietary Supplement ◽  
Competitive Inhibition ◽  
Hydrophobic Interactions ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Strong Hydrogen Bond ◽  
Cirsium Japonicum

In the search for natural products having a dual inhibitory action on diabetes and Alzheimer’s disease, this study investigated the activity of different parts of Korean thistle (Cirsium japonicum var. maackii (Maxim.) Matsum), and its fractional constituents by in vitro enzymatic and in silico molecular docking studies. Cirsium maackii has been used as a traditional medicine for the treatment of several diseases. The ethyl acetate and dichloromethane fractions of a leaf extract showed α-glucosidase and BACE1 inhibitory activity, respectively. Furthermore, the isolated compound, luteolin, exhibited concentration-dependent non-competitive inhibition against both α-glucosidase and BACE1 (IC50 = 51.27 ± 1.23 and 13.75 ± 0.26 μM; Ki value = 52.04 and 14.76 μM, respectively). Moreover, docking studies showed that luteolin formed a strong hydrogen bond with the peripheral binding amino acid residues, and hydrophobic interactions with the α-glucosidase and BACE1 enzymes. Therefore, Korean thistle may act as an important dietary supplement against diabetes and Alzheimer’s disease, especially the leaves, because of the preponderance of the active component, luteolin, making Korean thistle a promising candidate for more detailed in vitro and in vivo studies.

scholarly journals Mulberry Fruit Cultivar ‘Chiang Mai’ Prevents Beta-Amyloid Toxicity in PC12 Neuronal Cells and in a Drosophila Model of Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1837 ◽  
Author(s):  
Uthaiwan Suttisansanee ◽  
Somsri Charoenkiatkul ◽  
Butsara Jongruaysup ◽  
Somying Tabtimsri ◽  
Dalad Siriwan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Cells ◽  
Chiang Mai ◽  
Aβ Peptides ◽  
Amyloid Toxicity ◽  
Model Of Alzheimer’S Disease ◽  
Bace 1

Alzheimer’s disease (AD) is the most common form of dementia, characterized by chronic neuron loss and cognitive problems. Aggregated amyloid beta (Aβ) peptides, a product of cleaved amyloid precursor protein (APP) by beta-secretase 1 (BACE-1), have been indicated for the progressive pathogenesis of AD. Currently, screening for anti-AD compounds in foodstuffs is increasing, with promising results. Hence, the purpose of this study was to investigate the extraction conditions, phytochemical contents, and anti-AD properties, targeting Aβ peptides of Morus cf. nigra ‘Chiang Mai’ (MNCM) both in vitro and in vivo. Data showed that the aqueous extract of MNCM contained high amounts of cyanidin, keracyanin, and kuromanin as anthocyanidin and anthocyanins. The extract also strongly inhibited cholinesterases and BACE-1 in vitro. Moreover, MNCM extract prevented Aβ-induced neurotoxicity and promoted neurite outgrowth in neuronal cells. Interestingly, MNCM extract reduced Aβ1–42 peptides and improved locomotory coordination of Drosophila co-expressing human APP and BACE-1, specifically in the brain. These findings suggest that MNCM may be useful as an AD preventive agent by targeting Aβ formation.

In-silico studies and Biological activity of potential BACE-1 Inhibitors

2020 ◽  
Vol 23 ◽  
Author(s):  
Richa Arya ◽  
Sarvesh Paliwal ◽  
S.P Gupta ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
In Silico ◽  
Neuronal Damage ◽  
Pharmacophore Model ◽  
Vitro Assay ◽  
App Processing ◽  
In Silico Studies ◽  
Bace 1

Background: Alzheimer’s disease is neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in brain is caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). Objective: : The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease. Method: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with activity magnitude of greater than 4.of compounds. Results: In an advent to design new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by in-silico approach were evaluated by docking interactions. Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl substituted carbamate compound exhibited highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

scholarly journals Diplazium esculentum (Retz.) Sw. reduces BACE-1 activities and amyloid peptides accumulation in Drosophila models of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanit Kunkeaw ◽  
Uthaiwan Suttisansanee ◽  
Dunyaporn Trachootham ◽  
Jirarat Karinchai ◽  
Boonrat Chantong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Complex Disease ◽  
Cholinergic Neurons ◽  
Ethanolic Extract ◽  
Edible Plant ◽  
Bace 1

AbstractAlzheimer’s disease (AD), one type of dementia, is a complex disease affecting people globally with limited drug treatment. Thus, natural products are currently of interest as promising candidates because of their cost-effectiveness and multi-target abilities. Diplazium esculentum (Retz.) Sw., an edible fern, inhibited acetylcholinesterase in vitro, inferring that it might be a promising candidate for AD treatment by supporting cholinergic neurons. However, evidence demonstrating anti-AD properties of this edible plant via inhibiting of neurotoxic peptides production, amyloid beta (Aβ), both in vitro and in vivo is lacking. Thus, the anti-AD properties of D. esculentum extract both in vitro and in Drosophila models of Aβ-mediated toxicity were elucidated. Findings showed that an ethanolic extract exhibited high phenolics and flavonoids, contributing to antioxidant and inhibitory activities against AD-related enzymes. Notably, the extract acted as a BACE-1 blocker and reduced amyloid beta 42 (Aβ42) peptides in Drosophila models, resulting in improved locomotor behaviors. Information gained from this study suggested that D. esculentum showed potential for AD amelioration and prevention. Further investigations in vertebrates or humans are required to determine the effective doses of D. esculentum against AD, particularly via amyloidogenic pathway.

Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 inhibitor: Plausible lead for Alzheimer’s Disease.

2020 ◽  
Vol 17 ◽  
Author(s):  
Priti Jain ◽  
Pankaj K Wadhwa ◽  
Hemant R Jadhav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Aromatic Ring ◽  
Active Sites ◽  
Neurodegenerative Disorder ◽  
Pyrimidine Derivatives ◽  
Vitro Assay ◽  
Docking Score ◽  
Bace 1

: Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer’s disease (AD). Since, it catalyzes the rate limiting step of Aβ-42 production from amyloid precursor protein (APP),its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group. Objective: Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In vitro FRET based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition profile. Method: Based on the docking simulation studies, a library of derivatives was designed, synthesized and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide (Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated as a measure of activity. Results: The designed compounds revealed strong interactions with the desired amino acids of BACE-1 active sites. The aromatic rings placed at fourth and sixth position of pyrimidine ring occupied S1 and S3 substrate binding clefts while the amino group formed hydrogen bonding interactions with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10µM concentration. Conclusion: Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high docking score and was found to be most potent with IC50 of 6.92µM. The series displayed a good correlation between docking score and BACE-1 inhibition profile.

scholarly journals Ajmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1609
Author(s):  
Priya Kashyap ◽  
Vivekanandan Kalaiselvan ◽  
Robin Kumar ◽  
Suresh Kumar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico Analysis ◽  
Neuroprotective Activity ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Mao B ◽  
Disease Modifying ◽  
Bace 1

Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC50 values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H2O2 (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.

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