Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer’s disease therapeutics

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

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Recent Advances in the Development and Characterization of Electrochemical and Electrical Biosensors for Small Molecule Neurotransmitters

ACS Sensors, Journal Year: 2023, Volume and Issue: 8(4), P. 1391 - 1403

Published: March 20, 2023

Neurotransmitters act as chemical messengers, determining human physiological and psychological function, abnormal levels of neurotransmitters are related to conditions such Parkinson's Alzheimer's disease. Biologically clinically relevant concentrations usually very low (nM), so electrochemical electronic sensors for neurotransmitter detection play an important role in achieving sensitive selective detection. Additionally, these have the distinct advantage potentially be wireless, miniaturized, multichannel, providing remarkable opportunities implantable, long-term sensing capabilities unachievable by spectroscopic or chromatographic methods. In this article, we will focus on advances development characterization during last five years, identifying how field is progressing well critical knowledge gaps sensor researchers.

Language: Английский

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In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Oct. 21, 2022

Abstract Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles CK2α, which a protein encoded by CSNK2A1 , in the progression and aggressiveness CLL. Furthermore, various computational tools used search for competent inhibitor CK2α from fungal metabolites that could be proposed CLL therapy. patients, high-expression was associated with early need therapy (n = 130, p < 0.0001) short overall survival (OS; n 107, 0.005). Consistently, showed associate with/play proliferation survival-dependent pathways. PPI network analysis identified interaction partners (PPI enrichment value 1 × 10 –16 ) 0.003) have been known heavily impact on These findings constructed rational targeting Consequently, reported 35 out 5820 (filtered 19,967 metabolites) lower binding energy (ΔG: − 10.9 11.7 kcal/mol) better affinity (Kd: 9.77 7 M −1 3.77 8 compared native ligand 10.8, Kd: 8.3 M− ). molecular dynamics simulation study established Butyl Xanalterate-CK2α complex continuously remained stable throughout time (100 ns). Moreover, Xanalterate interacted most catalytic residues, where stabilized more than 65% hydrogen bond interactions, significant hydrophobic residue Phe113. Here, implicated poor prognosis CLL, making it potential therapeutic target disease. strong interactions thus we propose as competitive

Language: Английский

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Linagliptin and Empagliflozin Inhibit Microtubule Affinity Regulatory Kinase 4: Repurposing Anti-Diabetic Drugs in Neurodegenerative Disorders Using In Silico and In Vitro Approaches

ACS Omega, Journal Year: 2023, Volume and Issue: 8(7), P. 6423 - 6430

Published: Feb. 7, 2023

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are significant public health burdens. Many studies have revealed the possibility of common pathophysiology between T2DM AD. Thus, in recent years, deciphering action mechanism anti-diabetic drugs with their future use AD related pathologies on high demand. Drug repurposing is a safe effective approach owing to its low cost time-saving attributes. Microtubule affinity regulating kinase 4 (MARK4) druggable target for various diseases found be linked mellitus. MARK4 plays vital role energy metabolism regulation thus serves as an irrefutable treat T2DM. The present study was intended identify potent inhibitors among FDA-approved drugs. We performed structure-based virtual screening top hits against MARK4. identified five having appreciable specificity toward binding pocket Among these hits, two drugs, linagliptin, empagliflozin, favorably bind pocket, interacting critical residues subjected detailed analysis. All-atom molecular dynamics (MD) simulations linagliptin empagliflozin Kinase assay showed inhibition activity presence implying them inhibitors. In conclusion, may promising inhibitors, which can further exploited potential lead molecules MARK4-directed neurodegenerative diseases.

Language: Английский

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Investigation of Charged Small Molecule–Aptamer Interactions with Surface Plasmon Resonance

Analytical Chemistry, Journal Year: 2023, Volume and Issue: 95(5), P. 2639 - 2644

Published: Jan. 27, 2023

Investigating the interactions between small, charged molecules and aptamers using surface plasmon resonance (SPR) is limited by inherent low response of small difficulties with nonspecific electrostatic aptamer, analyte, sensor surface. However, are increasingly being used in sensors for molecule detection critical areas like healthcare environmental safety. The ability to probe these through simple, direct SPR assays would be greatly beneficial allow development improved without need complicated signal enhancement. nearly nonexistent current literature instead surpassed sandwich or competitive binding techniques, which require additional sample preparation reagents. In this work, we develop a method characterize interaction serotonin (176 Da) an aptamer streptavidin–biotin capture high-ionic-strength buffer. Additionally, other methods, such as immobilization thiol-coupling were investigated comparison. These techniques give insight into working quickly adapting affinity assay sensor.

Language: Английский

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Gut–brain communication mediates the impact of dietary lipids on cognitive capacity

Food & Function, Journal Year: 2024, Volume and Issue: 15(4), P. 1803 - 1824

Published: Jan. 1, 2024

The effects of dietary lipids on cognition, both positive and negative, are mediated through the gut–brain axis by modulating metabolic, immune, neural, endocrine pathways.

Language: Английский

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Targeting inhibition of microtubule affinity regulating kinase 4 by Harmaline: Strategy to combat Alzheimer's disease

International Journal of Biological Macromolecules, Journal Year: 2022, Volume and Issue: 224, P. 188 - 195

Published: Oct. 17, 2022

Language: Английский

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Inhibition of microtubule affinity regulating kinase 4 by an acetylcholinesterase inhibitor, Huperzine A: Computational and experimental approaches

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 235, P. 123831 - 123831

Published: March 3, 2023

Language: Английский

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Unraveling human transferrin-tryptamine interactions: a computational and biophysical approach to Alzheimer’s disease therapeutics

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 19, 2025

Neurodegeneration is a progressive loss of neurons that leads to affected cognitive and motor functions characterized by neurodegenerative disorders (NDs). Human transferrin (Htf) blood plasma glycoprotein binds iron regulates the free in biological fluids. Free potent neurotoxin associated with generation Reactive oxygen species (ROS) ultimately linked oxidative stress neuronal damage. Thus, targeting homeostasis an attractive strategy for management NDs, viz. Alzheimer's disease (AD). Tryptamine (Trp) naturally occurring monoamine, has demonstrated promising roles AD therapeutics. The present study aims delineate binding mechanism Trp Htf employing computational spectroscopic approaches. Molecular docking ascertained vital residues governing Htf-Trp complex formation. Further, dynamic (MD) studies structural dynamics stability complex, implying causes minimal alterations Htf, suggestive complex. results from fluorescence spectroscopy constant ( K ) 0.48 × 10 6 M −1 , validating silico observations. This provides platform understand may lead novel therapeutic approaches AD.

Language: Английский

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Experimental and theoretical studies on structural changes in the microtubule affinity-regulating kinase 4 (MARK4) protein induced by N-hetarenes: a new class of therapeutic candidates for Alzheimer’s disease

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 19, 2025

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively affects the cognitive function and memory of affected person. Unfortunately, only handful effective prevention or treatment options are available today. Microtubule affinity-regulating kinase 4 (MARK4) serine/threonine protein plays critical role in regulating microtubule dynamics facilitating cell division. The dysregulated expression MARK4 has been associated with range diseases, including AD. Methods In this study, we synthesized series N -hetarenes via Pd(0)-catalyzed Suzuki-Miyaura cross coupling reaction. All compounds were characterized using multi-spectroscopic techniques evaluated for their activity against enzyme through ATPase inhibition assays. experimental data was further supported by computational quantum chemical calculations. We also computed drug-likeness, bioavailability, toxicity (ADME/T) profiles compounds. Results Six new 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides 5−10 prepared good yields. assay conducted on these demonstrated IC 50 values micromolar (5.35 ± 0.22 to 16.53 1.71 μM). Among tested compounds, 4-(6-( p -tolyl)pyrimidin-4-yl)piperazine-1-carboximidamide ( 5 ; = 5.35 μM) 4-(6-(benzo[ b ]thiophen-2-yl)pyrimidin-4-yl)piperazine-1-carboximidamide 9 6.68 0.80 showed best activity. binding constant K ), as determined fluorescence quenching estimated be 1.5 0.51 × 10 M −1 1.14 0.26 . results molecular docking MD simulation studies (PDB: 5ES1) indicated able bind ATP pocket MARK4, leading its stabilization. Additionally, ADME/T analysis revealed high degree drug-likeness Conclusion 4-(6-(arylpyrimidin-4-yl)piperazine-1-carboximidamides) promising class developing next-generation anti-AD drugs. reported inhibited in-vitro at concentration targeting ATP-binding pocket. These findings provide valuable insights future drug design.

Language: Английский

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