Natural polyphenols as inhibitors of amyloid aggregation. Molecular dynamics study of GNNQQNY heptapeptide decamer

Berhanu, Workalemahu M.; Masunov, Artëm E.

doi:10.1016/j.bpc.2010.03.003

Cited by 51 publications

(66 citation statements)

References 48 publications

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“…They were also reported to act as inhibitors for amyloid aggregation (Berhanu et al, 2010). They, however, show limited absorption and low bioavailability in the brain (Baptista et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

Kumar

Srivastava

Tripathi

et al. 2015

Journal of Biomolecular Structure and Dynamics

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Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer's disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A-B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer.

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Section: Introductionmentioning

confidence: 98%

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

Kumar

Srivastava

Tripathi

et al. 2015

Journal of Biomolecular Structure and Dynamics

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“…A multimethodological study also proved that myricetin inhibits Aβ aggregation by targeting preferentially Aβ monomers and short transient oligomers [88]. Computational analysis showed that myricetin interacts with the surface of the β-sheet via H-bonding, weakening the interstrand hydrogen bonds and eventually disrupting the outer layer of the aggregate [89]. In addition, the integrated catechol moiety of flavonoids performs a bifunctional inhibitory activity (metal chelation and Aβ interaction) against Aβ aggregation by interacting with the metal binding site on Aβ via their α-keto enolate group [90,91].…”

Section: Flavonoidsmentioning

confidence: 93%

“…Furthermore, oxidizing the residue methionine (Met 35 ) in Aβ monomers, which hinders the amyloidogenic conformation, is also the potential mechanism for anti-aggregation of myricetin as revealed by mass spectrometry experiments [92]. Other flavonoids with potential Aβ aggregation inhibition include baicalein [93], morin [94], apigenin [95], and kaempferol [89] shown in Fig. 2.…”

Section: Flavonoidsmentioning

confidence: 96%

Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer’s Drug Discovery

Rao

Wang

2015

Mol Neurobiol

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Several plant-derived natural compounds are known to exhibit anti-amyloid aggregation activity which makes them attractive as potential therapies to treat Alzheimer's disease. The mechanisms of their anti-amyloid activity are not well known. In this regard, many natural compounds are known to exhibit direct binding to various amyloid species including oligomers and fibrils, which in turn can lead to conformational change in the beta-sheet assembly to form nontoxic aggregates. This review discusses the mechanism of anti-amyloid activity of 16 natural compounds and gives structural details on their direct binding interactions with amyloid aggregates. Our computational investigations show that the physicochemical properties of natural products do fit Lipinski's criteria and that catechol and catechol-type moieties present in natural compounds act as lysine site-specific inhibitors of amyloid aggregation. Based on these observations, we propose a structural template to design novel small molecules containing site-specific ring scaffolds, planar aromatic and nonaromatic linkers with suitably substituted hydrogen bond acceptors and donors. These studies will have significant implications in the design and development of novel amyloid aggregation inhibitors with superior metabolic stability and blood-brain barrier penetration as potential agents to treat Alzheimer's disease.

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“…The RMSDs and RMSF provide useful information on relative stability of the oligomers, and were previously used in the stability analysis of short amyloid oligomers with β-sheet structure (Berhanu & Masunov, 2010, 2012b. To compare the effect of polyphenols' binding to the VQIVYK oligomer, we calculated the RMSD of C α of the apo-form and in complex with the ligand of the oligomer as shown in Figure 1(A).…”

Section: Rmsd and Rmsfmentioning

confidence: 99%

“…Recently, we performed an implicit solvent MD simulations of amyloid oligomers, and analyzed disaggregation effect of polyphenol Myricetin (Berhanu & Masunov, 2010). We found that Myricetin forms H bonds with the outer β-sheet and weakens its interstrand H bonds.…”

Section: Introductionmentioning

confidence: 97%

Atomistic mechanism of polyphenol amyloid aggregation inhibitors: molecular dynamics study of Curcumin, Exifone, and Myricetin interaction with the segment of tau peptide oligomer

Berhanu

Masunov

2014

Journal of Biomolecular Structure and Dynamics

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Amyloid fibrils are highly ordered protein aggregates associated with many diseases affecting millions of people worldwide. Polyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimer's disease. However, the molecular mechanisms of this inhibition remain elusive. We investigated the binding of three polyphenol molecules to the protofibrils of an amyloidogenic fragment VQIVYK of tau peptide by molecular dynamics simulations in explicit solvent. We find that polyphenols induce conformational changes in the oligomer aggregate. These changes disrupt the amyloid H bonding, perturbing the aggregate. While the structural evolution of the control oligomer with no ligand is limited to the twisting of the β-sheets without their disassembly, the presence of polyphenol molecule pushes the β-sheets apart, and leads to a loosely packed structure where two of four β-sheets dissociate in each of the three cases considered here. The H-bonding capacity of polyphenols is responsible for the observed behavior. The calculated binding free energies and its individual components enabled better understanding of the binding. Results indicated that the contribution from Van der Waals interactions is more significant than electrostatic contribution to the binding. The findings from this study are expected to assist in the development of aggregation inhibitors. Significant binding between polyphenols and aggregate oligomer identified in our simulations confirms the previous experimental observations in which polyphenols refold the tau peptide without forming covalent bonds.

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Natural polyphenols as inhibitors of amyloid aggregation. Molecular dynamics study of GNNQQNY heptapeptide decamer

Cited by 51 publications

References 48 publications

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4′ benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations

Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer’s Drug Discovery

Atomistic mechanism of polyphenol amyloid aggregation inhibitors: molecular dynamics study of Curcumin, Exifone, and Myricetin interaction with the segment of tau peptide oligomer

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