Dammarane triterpenes targeting α-synuclein: biological activity and evaluation of binding sites by molecular docking

Cornejo, Alberto; Caballero, Julio; Simirgiotis, Mario J.; Torres, Vanessa; Sanchez, L.E Mallea; Díaz, Nicolás; Guimaraes, Marcela; Hernández, Marcos; Areche, Carlos; Alfaro, Sergio; Caballero, Leonardo; Melo, Francisco

doi:10.1080/14756366.2020.1851216

Cited by 8 publications

(9 citation statements)

References 40 publications

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“…PD is the second-fastest-growing neurodegenerative disorder worldwide after Alzheimer's disease and highly affects the elderly (Cornejo et al, 2021). The alpha-synuclein oligomer and fibrils are crucial for PD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacotherapeutics and molecular docking studies of alpha-synuclein modulators as promising therapeutics for Parkinson’s disease

ALI¹,

Alam²,

RAJPUT³

et al. 2022

Biocell

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Parkinson's disease (PD) is an age-related neurodegenerative ailment that affects dopamine-producing neurons in a specific area of the brain called the substantia nigra of the ventral midbrain. It is clinically characterized by movement disorder and marked with unusual synaptic protein alpha-synuclein accumulation in the brain. To date, only a few Food and Drug Administration (FDA) approved drugs are available on the market for the treatment of PD. Nonetheless, these drugs show parasympathomimetic related adverse events and remarkably higher toxicity; hence, it is important to find more efficacious molecules to treat PD. In our study, We chosen 22 natural compounds as inhibitors that potentially block the alpha-synuclein clump-the pathological hallmark of PD-and provide new avenues for its treatment. Most of these molecules exhibited good pharmacokinetic behaviors, making them decisively favorable drug candidates to cure PD. Molecular docking studies were performed to investigate the binding interactions between natural compounds and alpha-synuclein as anti-Parkinson drug targets. Among the examined compounds, curcumin and piperine emerged as promising phytochemicals with the highest binding affinity, key residual stable bindings and showed a good inhibitory features. Thus, the present study indicates that curcumin and piperine hold the potential to be developed as treatment options against PD. Experimental validations are needed for insights into their mechanism of action and potential clinical application.

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Section: Discussionmentioning

confidence: 99%

“…To date, available treatments for neurodegenerative diseases are not appropriately effective and have side effects. The standard gold treatment of PD using levodopa has copious side effects (Cornejo et al, 2021). Most of the drugs have failed to inhibit or limit the progress of Perkinson's disease (Niedzielska et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Pharmacotherapeutics and molecular docking studies of alpha-synuclein modulators as promising therapeutics for Parkinson’s disease

ALI¹,

Alam²,

RAJPUT³

et al. 2022

Biocell

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“…Natural compounds were widely used in food, cosmetics and other industries for many years. Because of their high safety, many clinical and preclinical studies begun to pay attention to them (60)(61)(62)(63)(64). As a natural polysaccharide extracted from brown algae, fucoidan was proved to have many biological effects (12)(13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Fucoidan Inhibits the Progression of Hepatocellular Carcinoma via Causing lncRNA LINC00261 Overexpression

Wei

Chen

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) as a main type of primary liver cancers has become one of the most deadly tumors because of its high morbidity and poor prognosis. Fucoidan is a family of natural, heparin-like sulfated polysaccharides extracted from brown algae. It is not only a widely used dietary supplement, but also participates in many biological activities, such as anti-oxidation, anti-inflammation and anti-tumor. However, the mechanism of fucoidan induced inhibition of HCC is elusive. In our study, we demonstrated that fucoidan contributes to inhibiting cell proliferation in vivo and in vitro, restraining cell motility and invasion and inducing cell cycle arrest and apoptosis. According to High-Throughput sequencing of long-non-coding RNA (lncRNA) in MHCC-97H cells treated with 0.5 mg/mL fucoidan, we found that 56 and 49 lncRNAs were correspondingly up- and down-regulated. LINC00261, which was related to the progression of tumor, was highly expressed in fucoidan treated MHCC-97H cells. Moreover, knocking down LINC00261 promoted cell proliferation by promoting the expression level of miR-522-3p, which further decreased the expression level of downstream SFRP2. Taken together, our results verified that fucoidan effectively inhibits the progression of HCC via causing lncRNA LINC00261 overexpression.

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“…All atomic force images were obtained in a Nanoscope IIIa as described, [37] in a fluid cell using the tapping mode through SiN cantilever, whose stiffness constant ranges from 0.12 to 0.15 N/m. The tapping mode provides the phase information, making it possible to distinguish between the sample elements and thereby their morphology.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were cultured and differentiated in Petri dishes 35/10 mm over coverslips, then the cells were cultures with a Neurobasal medium plus 10 μM of retinoic acid for five days replacing medium culture every 48 h for neurite growth. [37] After that, cells were fixed for immunofluorescence and, the supernatant recovered for LDH measurement. The cells and neurite-like structure were monitored with a Euromex microscope.…”

Section: Cell Culture Immunofluorescence and Ldh Measurementsmentioning

confidence: 99%

α‐Synuclein Drives Tau's Cytotoxic Aggregates Formation through Hydrophobic Interactions

Ojeda,

Cofré,

Melo

et al. 2023

ChemPlusChem

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Tau and α‐synuclein are proteins involved in pathologies known as tauopathies and synucleinopathies, respectively. Moreover, evidence shows that there is a crosstalk between them as is seen in the brains of individuals with sporadic neurodegenerative disorders. Based on that, we present data showing that the hydrophobic α‐peptide 71VTGVTAVAQKTV82 induces the aggregation of the full‐length tau fragment in the absence of heparin assessed by ThT. Moreover, AFM images reveal the presence of straight filaments and amorphous aggregates of full‐length tau in the presence of the α‐peptide. Additionally, ITC experiments showed the interaction of the α‐peptide with tau full‐length (441),4R (244‐369), and both hexapeptides 275VQIINK280 and 306VQIVYK311 through hydrophobic interactions. The Raman spectroscopy spectra showed conformational changes in the Amide region in the aggregates formed with full‐length tau and α‐syn peptide. Furthermore, the incubation of extracellular aggregates with N2a cells showed morphological differences in the cellular body and the nucleus. Also, the incubation of different types of aggregates in cell culture provokes the release of Lactate dehydrogenase (LDH). Altogether, we found that α‐synuclein peptide can drive the aggregation of full‐length tau‐provoking morphological and structural changes evoking cytotoxic effects.

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Dammarane triterpenes targeting α-synuclein: biological activity and evaluation of binding sites by molecular docking

Cited by 8 publications

References 40 publications

Pharmacotherapeutics and molecular docking studies of alpha-synuclein modulators as promising therapeutics for Parkinson’s disease

Pharmacotherapeutics and molecular docking studies of alpha-synuclein modulators as promising therapeutics for Parkinson’s disease

Fucoidan Inhibits the Progression of Hepatocellular Carcinoma via Causing lncRNA LINC00261 Overexpression

α‐Synuclein Drives Tau's Cytotoxic Aggregates Formation through Hydrophobic Interactions

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