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Journal ArticleDOI: 10.1080/07391102.2020.1728384

Computational investigation on the effect of Oleuropein aglycone on the α-synuclein aggregation.

04 Mar 2021-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 39, Iss: 4, pp 1259-1270
Abstract: Parkinson’s disease (PD) is considered to be the second most common progressive neurodegenerative brain disorder after Alzheimer’s disease, which is caused by misfolding and aggregation of Alpha-sy...

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Topics: Protein aggregation (56%)
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7 results found


Journal ArticleDOI: 10.1021/ACSCHEMNEURO.0C00598
Yifei Yao1, Yiming Tang1, Guanghong Wei1Institutions (1)
Abstract: The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson's disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported that epigallocatechin gallate (EGCG), a polyphenol extracted from green tea, can disrupt α-syn fibrils into benign amorphous aggregates. However, the molecular mechanism of action is poorly understood. Herein, we performed molecular dynamics simulations on a newly released Greek-key-like α-syn fibril with or without EGCG to investigate the influence of EGCG on α-syn fibril. Our simulations show that EGCG disrupts the local β-sheet structure, E46-K80 salt-bridge crucial for the stabilization of the Greek-key-like structure, and hydrophobic interactions stabilizing the inter-protofibril interface and destabilizes the global structure of the α-syn fibril. Interaction analyses reveal that hydrophobic and hydrogen-bonding interactions between EGCG and α-syn fibrils play important roles in the destabilization of the fibril. We find that the disruption of the E46-K80 salt-bridge closely correlates with the formation of hydrogen-bonds (H-bonds) between EGCG and E46/K80. Our results provide mechanistic insights into the disruption modes of α-syn fibril by EGCG, which may pave the way for designing drug candidates targeting α-syn fibrillization to treat PD.

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Topics: Fibril (56%)

5 Citations


Journal ArticleDOI: 10.1039/D0FO01511C
23 Sep 2020-Food & Function
Abstract: In the central nervous system (CNS), extra virgin olive oil (EVOO) produces interesting effects against neurodegenerative disorders including Alzheimer's disease (AD). The valuable properties of EVOO are largely ascribed to oleuropein aglycone (OA), its most abundant phenolic constituent. In particular, it has been demonstrated that in AD, OA produces strong neuroprotective effects being able to reduce amyloid β (Aβ) aggregates, thereby diminishing the related cytotoxicity and inflammation. OA prevents Aβ aggregation, but more importantly OA was able to disrupt the preformed Aβ fibrils. Herein, we describe a comprehensive computational investigation of the mechanism of action of OA as an Aβ fibril disruptor at the molecular level. We employed extensive molecular docking calculations and long-time molecular dynamics simulation for mimicking the system of OA/Aβ fibrils. The results showed that OA is able to move in depth within the Aβ fibrils targeting a key motif in Aβ peptide, known to be relevant for stabilizing the assembled fibrils. OA causes a structural instability of preformed Aβ fibrils, determining the effective Aβ fibril disaggregation. Accordingly, this study highlighted the role of OA as a potent anti-amyloidogenic drug. On the other hand, our work has relevant implications for rationally designing potent multifunctional compounds acting as disease modifying anti-Alzheimer's drugs for the development of innovative anti-AD therapeutics.

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4 Citations


Journal ArticleDOI: 10.1016/J.IJBIOMAC.2020.10.139
Abstract: Herbal bioactive compounds have captured pronounced attention considering their health-promoting effects as well as their functional properties. In this study, the binding mechanism between milk protein bovine β-lactoglobulin (β-LG), oleuropein (OLE) and safranal (SAF) found in olive leaf extract and saffron, respectively via spectroscopic and in silico studies. Fluorescence quenching information exhibited that interactions with both ligands were spontaneous and hydrophobic interactions were dominant. Also, the CD spectroscopy results demonstrated the increase in β-sheet structure and decrease in the α-helix content for both ligands. Size of β-LG-OLE complex was higher than β-LG-SAF due to the conformation and larger molecular size. Molecular docking and simulation studies revealed that SAF and OLE bind in the central calyx of β-LG and the surface of β-LG next to hydrophobic residues. Lastly, OLE formed a more stabilized complex compared to SAF based on the molecular dynamic simulation results.

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Topics: Safranal (51%)

2 Citations


Open accessJournal ArticleDOI: 10.1016/J.JKSUS.2020.101270
Abstract: Riboflavin synthase is an important enzyme catalyzing the last step of riboflavin biosynthesis in microorganisms. Due to the absolute dependency of the microbes to this biosynthetic pathway coupled with its nonexistence in humans, riboflavin synthase (RiS) is considered as a prospective drug target. The riboflavin synthase for this study was derived from Leptospira kmetyi, a pathogenic bacterium locally isolated in Malaysia. Leptospirosis, an infectious disease caused by pathogenic Leptospira, is a serious growing public health issue. Treatment of leptospirosis with antibiotics over time resulted in the evolution of antibiotic resistance strains, thus requiring the development of newer but safe antimicrobial agents. In this study, a computational approach involving virtual screening followed by molecular dynamics (MD) simulation was implemented in order to identify possible inhibitors against riboflavin synthase. The model of Leptospira kmetyi riboflavin synthase predicted from E. coli riboflavin synthase (1I8D) was used as the drug target to screen for potential compounds from the ZINC database through virtual screening. The potential compound with the highest Glide score (−10.987 Kcal/mol) was identified to be ZINC21883831. Chemically it is 2-[(2-chloro-4-fluoro-phenyl)methylsulfanyl]-7-phenyl-3,5-dihydropyrrolo[2,3-e]pyrimidin-4-one. The top three docked complexes from the virtual screening and apo-structures were subjected to molecular dynamics simulation to predict the stabilities of the Leptospira kmetyi riboflavin synthase-ligand complexes. Stability parameters including RMSD, RMSF, SASA and Rg of the complexes were evaluated from 60 ns of the MD simulation trajectories. Insights from this study provide promising starting points for the rational designs of new effective and safe anti-leptospirosis drugs.

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Topics: Riboflavin synthase (69%), Virtual screening (51%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/ANTIOX10030421
10 Mar 2021-Antioxidants
Abstract: Neurodegenerative diseases are driven by several mechanisms such as inflammation, abnormal protein aggregation, excitotoxicity, mitochondrial dysfunction and oxidative stress. So far, no therapeutic strategies are available for neurodegenerative diseases and in recent years the research is focusing on bioactive molecules present in food. In particular, extra-virgin olive oil (EVOO) phenols have been associated to neuroprotection. In this study, we investigated the potential antioxidant and neuroprotective activity of two different EVOO extracts obtained from Quercetano cultivar trees grown in two different areas (plain and hill) of the Tuscany region (Italy). The different geographical origin of the orchards influenced phenol composition. Plain extract presented a higher content of phenyl ethyl alcohols, cinnammic acids, oleacein, oleocanthal and flavones; meanwhile, hill extract was richer in lignans. Hill extract was more effective in protecting differentiated SH-SY5Y cells from peroxide stress thanks to a marked upregulation of the antioxidant enzymes heme oxygenase 1, NADPH quinone oxidoreductase 1, thioredoxin Reductase 1 and glutathione reductase. Proteomic analysis revealed that hill extract plays a role in the regulation of proteins involved in neuronal plasticity and activation of neurotrophic factors such as BDNF. In conclusion, these data demonstrate that EVOOs can have important neuroprotective activities, but these effects are strictly related to their specific phenol composition.

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Topics: Oleocanthal (53%), Glutathione reductase (51%), Antioxidant (51%) ... read more

1 Citations


References
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64 results found


Open accessJournal ArticleDOI: 10.1093/NAR/28.1.235
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.

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30,190 Citations


Journal ArticleDOI: 10.1063/1.445869
Abstract: Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.

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Topics: Water model (53%), Solvent models (52%), Water dimer (51%) ... read more

29,424 Citations


Open accessJournal ArticleDOI: 10.1002/JCC.20084
Abstract: The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.

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Topics: Unix (50%), OS X (50%)

28,452 Citations


Open accessJournal ArticleDOI: 10.1063/1.464397
Tom Darden1, Darrin M. York1, Lee G. Pedersen1Institutions (1)
Abstract: An N⋅log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolutions using fast Fourier transforms. Timings and accuracies are presented for three large crystalline ionic systems.

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Topics: Ewald summation (69%), P3M (64%), Particle Mesh (51%)

20,639 Citations


Open accessJournal ArticleDOI: 10.1016/0021-9991(77)90098-5
Abstract: A numerical algorithm integrating the 3N Cartesian equations of motion of a system of N points subject to holonomic constraints is formulated. The relations of constraint remain perfectly fulfilled at each step of the trajectory despite the approximate character of numerical integration. The method is applied to a molecular dynamics simulation of a liquid of 64 n-butane molecules and compared to a simulation using generalized coordinates. The method should be useful for molecular dynamics calculations on large molecules with internal degrees of freedom.

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Topics: Generalized coordinates (62%), Holonomic constraints (58%), Verlet integration (58%) ... read more

16,572 Citations


Performance
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No. of citations received by the Paper in previous years
YearCitations
20214
20203