Modulation in the conformational and stability attributes of the Alzheimer’s disease associated amyloid-beta mutants and their favorable stabilization by curcumin: molecular dynamics simulation analysis

Awasthi, Manika; Singh, Swati; Pandey, Veda P.; Dwivedi, Upendra N.

doi:10.1080/07391102.2017.1279078

Cited by 32 publications

(17 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Awasthi and colleagues (2017) [69] studied two familial Aβ42 mutations, namely A2V (harmful) and A2T (protective) have been analyzed and compared with the WT by performing all-atom molecular dynamics simulations in the absence and presence of curcumin, a well-known inhibitor of Aβ plaque formation. Mutant A2V was found to exhibit highest stability followed by WT and mutant A2T in the absence of curcumin.…”

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

“…This stability trend was found to be reversed in the presence of curcumin, suggesting a significant change in the conformational landscape of Aβ42 folding. Due to significant differences in the folding and interaction patterns of the mutants A2V and A2T, curcumin exhibited higher binding affinity for mutant A2T as compared to that of A2V [69]. …”

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

See 1 more Smart Citation

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Reddy

Mańczak

Yin

et al. 2018

JAD

277

138

View full text Add to dashboard Cite

The purpose of our article is to assess the current understanding of Indian spice ‘Curcumin’ against amyloid-β (Aβ)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, anti-oxidant, anti-arthritis, pro-healing and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on amyloid-β and curcumin has revealed that curcumin prevents amyloid-β aggregation and crosses the blood brain barrier (BBB), reach brain cells and protect neurons from various toxic insults of aging and amyloid-β in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin’s bioavailability and urgent need for new formulation to increase its brain levels to treat patients with AD.

show abstract

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

Section: Curcumin and Its Derivatives Design And Synthesismentioning

confidence: 99%

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Reddy

Mańczak

Yin

et al. 2018

JAD

277

138

View full text Add to dashboard Cite

show abstract

“…Atomistic computer simulations are well-suited to provide molecular-level details of amyloid oligomer and fibril interactions with ligands, helping in the future development and characterization of druggable modalities [ 5 ]. Basically, four aspects of the flavonoid–amyloid interactions have been studied by computational methods: (1) the effect of ligands on the conformational transitions of Aβ monomers from an initial random coil or α-helix into β-sheet structures [ 6 , 7 ] and ligand-mediated conformational changes of the Aβ dimer [ 8 ] by means of replica exchange molecular dynamics (REMD) simulations; (2) the effect of ligands on the aggregation of Aβ(17–36) using coarse-grained simulations [ 9 ]; (3) the effect of ligands on the conformation and stability of amyloid-beta mutants [ 10 ] by molecular dynamics (MD) simulations; (4) the preferential binding sites of ligands and their effect on amyloid structure dynamics [ 11 ], Aβ fragments, and full-length single Aβ protofilaments [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ] by means of docking experiments, MD simulations, and free energy calculations.…”

Section: Introductionmentioning

confidence: 99%

Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40) Fibrils

2018

View full text Add to dashboard Cite

One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-epigallocatechin-3-gallate, quercetin, and rosmarinic acid) with amyloid-β(1–40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.

show abstract

“…Therefore, strong AChE inhibitors are needed to treat AD without any side effects. Computational methods are very useful techniques to elucidate receptor-ligand interactions at the atomic level that are difficult to solve using experimental techniques [24][25][26]. Thus, aim of the study is to find novel hit compounds against AChE using rigorous virtual screening approaches.…”

Section: Introductionmentioning

confidence: 99%

Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors

Şahin

Durdağı

2020

Turk J Chem

View full text Add to dashboard Cite

The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer’s disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer adverse side effects for the effective treatment. In this study, combined ligand-based and structure-based virtual screening approaches were used to identify new hit compounds from small molecules library of National Cancer Institute (NCI) containing approximately 265,000 small molecules. In the present study, we developed a computational pipeline method to predict the binding affinities of the studied compounds at the specific target sites. For this purpose, a text mining study was carried out initially and compounds containing the keyword “indol” were considered. The therapeutic activity values against AD were screened using the binary quantitative structure activity relationship (QSAR) models. We then performed docking, molecular dynamics (MD) simulations and free energy analysis to clarify the interactions between selected ligands and enzyme. Thus, in this study we identified new promising hit compounds from a large database that may be used to inhibit the enzyme activity of AChE.

show abstract

Modulation in the conformational and stability attributes of the Alzheimer’s disease associated amyloid-beta mutants and their favorable stabilization by curcumin: molecular dynamics simulation analysis

Cited by 32 publications

References 62 publications

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40) Fibrils

Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors

Contact Info

Product

Resources

About