Stepwise sequential analysis of stable multiradicals formation in polyphenolic myricetin active OH groups throughout the antioxidant process to scavenge free radicals

Barzegar, Abolfazl; Rezaei-Sadabady, Rogaie

doi:10.1016/j.molstruc.2017.06.011

Cited by 5 publications

(5 citation statements)

References 24 publications

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“…The initial structures of polyphenolic myricetin and morin flavonoids (Flvs) were generated and geometries were optimized using the semi-empirical AM1 followed by ab initio DFT method with Becke's three-parameter hybrid function 17 – 19 (Fig. S2 ).…”

Section: Methodsmentioning

confidence: 99%

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Gargari

Barzegar

2020

Sci Rep

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Structural studies of the aggregation inhibition of the amyloid-β peptide (Aβ) by different natural compounds are of the utmost importance due to their great potential as neuroprotective and therapeutic agents for Alzheimer’s disease. We provided the simulation of molecular dynamics for two different states of Aβ42, including “monomeric aggregation-prone state (APS)” and “U-shaped pentamers of amyloidogenic protofilament intermediates” in the absence and presence of polyphenolic flavonoids (Flvs, myricetin and morin) in order to verify the possible mechanism of Flvs fibrillogenesis suppression. Data showed that Flvs directly bind into Aβ42 species in both states of “monomeric APS β-sheets” and “pentameric amyloidogenic intermediates”. Binding of Flvs with amyloidogenic protofilament intermediates caused the attenuation of some inter-chains H-bonds, salt bridges, van der Waals and interpeptide interaction energies without interfering with their secondary β-sheets. Therefore, Flvs redirect oligomeric amyloidogenic intermediates into unstructured aggregates by significant disruption of the "steric zipper" motif of fibrils—pairs of self-complementary β-sheets—without changing the amount of β-sheets. It is while Flvs completely destruct the disadvantageous secondary β-sheets of monomeric APS conformers by converting them into coil/helix structures. It means that Flvs suppress the fibrillogenesis process of the monomeric APS structures by converting their β-sheets into proper soluble coil/helices structures. The different actions of Flvs in contact with two different states of Aβ conformers are related to high interaction tendency of Flvs with additional H-bonds for monomeric APS β-sheet, rather than oligomeric protofilaments. Linear interaction energy (LIE) analysis confirmed the strong binding of monomeric Aβ-Flvs with more negative ∆Gbinding, rather than oligomeric Aβ-Flvs system. Therefore, atomic scale computational evaluation of Flvs actions demonstrated different dual functions of Flvs, concluded from the application of two different monomeric and pentameric Aβ42 systems. The distinct dual functions of Flvs are proposed as suppressing the aggregation by converting β-sheets of monomeric APS to proper soluble structures and disrupting the "steric zipper" fibril motifs of oligomeric intermediate by converting on-pathway into off-pathway. Taken together, our data propose that Flvs exert dual and more effective functions against monomeric APS (fibrillogenesis suppression) and remodel the Aβ aggregation pathway (fibril destabilization).

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Section: Methodsmentioning

confidence: 99%

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Gargari

Barzegar

2020

Sci Rep

Self Cite

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“…Han et al observed myricetin-induced autophagy and apoptosis in human GC cells . Furthermore, myricetin can regulate the production of ROS in an oxidase-dependent manner. − The generation of ROS is critical for lipid peroxidation and the onset of ferroptosis . Multiple flavonoids have demonstrated a correlation with ferroptosis and lipid peroxidation in cancer cells .…”

Section: Introductionmentioning

confidence: 99%

Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4

Lu,

Sun,

Yang

et al. 2024

J. Agric. Food Chem.

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Ferroptosis holds great potential as a therapeutic approach for gastric cancer (GC), a prevalent and deadly malignant tumor associated with high rates of incidence and mortality. Myricetin, well-known for its multifaceted biomedical attributes, particularly its anticancer properties, has yet to be thoroughly investigated regarding its involvement in ferroptosis. The aim of this research was to elucidate the impact of myricetin on ferroptosis in GC progression. The present study observed that myricetin could trigger ferroptosis in GC cells by enhancing malondialdehyde production and Fe 2+ accumulation while suppressing glutathione levels. Mechanistically, myricetin directly interacted with NADPH oxidase 4 (NOX4), influencing its stability by inhibiting its ubiquitin degradation. Moreover, myricetin regulated the inhibition of ferroptosis induced by Helicobacter pylori cytotoxin-associated gene A (CagA) through the NOX4/NRF2/GPX4 pathway. In vivo experiments demonstrated that myricetin treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice. It was accompanied by increased NOX4 expression in tumor tissue and suppression of the NRF2/GPX4 antioxidant pathway. Therefore, this research underscores myricetin as a novel inducer of ferroptosis in GC cells through its interaction with NOX4. It is a promising candidate for GC treatment.

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“…8,9 Recent studies have demonstrated that polyphenols (e.g., flavonoids) can undergo multiple HAT reactions and scavenge several free radicals. 10,11 The reactions between free radicals and polyphenols involve diverse HAT steps. The HAT reaction between free radicals and polyphenol antioxidants is carried out in several steps.…”

Section: Introductionmentioning

confidence: 99%

“…Considerable research has been conducted on the single HAT reaction of flavonoids, whose AA is generally determined by the most active dissociable hydrogen atom of the –OH groups on the flavonoids. , Recent studies have demonstrated that polyphenols (e.g., flavonoids) can undergo multiple HAT reactions and scavenge several free radicals. , The reactions between free radicals and polyphenols involve diverse HAT steps. The HAT reaction between free radicals and polyphenol antioxidants is carried out in several steps.…”

Section: Introductionmentioning

confidence: 99%

Flavonoid as a Potent Antioxidant: Quantitative Structure–Activity Relationship Analysis, Mechanism Study, and Molecular Design by Synergizing Molecular Simulation and Machine Learning

Lu,

Luan,

Wang

et al. 2024

J. Phys. Chem. A

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In this work, a quantitative structure−antioxidant activity relationship of flavonoids was performed using a machine learning (ML) method. To achieve lipid-soluble, highly antioxidant flavonoids, 398 molecular structures with various substitute groups were designed based on the flavonoid skeleton. The hydrogen dissociation energies (ΔG 1 , ΔG 2 , and ΔG 3 ) related to multiple hydrogen atom transfer processes and the solubility parameter (δ) of flavonoids were calculated using molecular simulation. The group decomposition results and the calculated antioxidant parameters constituted the ML data set. The artificial neural network and random forest models were constructed to predict and analyze the contribution of the substitute groups and positions to the antioxidant activity. The results showed the hydroxyl group at positions B4′, B5′, and B6′ and the branched alkyl group at position C3 in the flavonoid skeleton were the optimal choice for improving antioxidant activity and compatibility with apolar organic materials. Compared to the pyrogallol group-grafted flavonoid, the designed potent flavonoid decreased ΔG 1 and δ by 2.2 and 15.1%, respectively, while ΔG 2 and ΔG 3 kept the favorable lower values. These findings suggest that an efficient flavonoid prefers multiple ortho-phenolic hydroxyl groups and suitable sites with hydrophobic groups. The combination of molecular simulation and the ML method may offer a new research approach for the molecular design of novel antioxidants.

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Stepwise sequential analysis of stable multiradicals formation in polyphenolic myricetin active OH groups throughout the antioxidant process to scavenge free radicals

Cited by 5 publications

References 24 publications

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4

Flavonoid as a Potent Antioxidant: Quantitative Structure–Activity Relationship Analysis, Mechanism Study, and Molecular Design by Synergizing Molecular Simulation and Machine Learning

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