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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Pharmacological features, health benefits and clinical implications of honokiol

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: 41(15), P. 7511 - 7533

Published: Sept. 12, 2022

Honokiol (HNK) is a natural polyphenolic compound extracted from the bark and leaves of Magnolia grandiflora. It has been traditionally used as medicinal to treat inflammatory diseases. HNK possesses numerous health benefits with minimal level toxicity. can cross blood-brain barrier blood-cerebrospinal fluid, thus having significant bioavailability in neurological tissues. promising bioactive neuroprotective, antimicrobial, anti-tumorigenic, anti-spasmodic, antidepressant, analgesic, antithrombotic features . prevent growth several cancer types haematological malignancies. Recent studies suggested its role COVID-19 therapy. binds effectively molecular targets, including apoptotic factors, chemokines, transcription cell surface adhesion molecules, kinases. excellent pharmacological wide range chemotherapeutic effects, thus, researchers have increased interest improving therapeutic implications clinic novel agent. This review focused on HNK, highlighting clinical underlying mechanism action.Communicated by Ramaswamy H. Sarma

Language: Английский

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Drug repurposing study of levofloxacin: Structural properties, lipophilicity along with experimental and computational DNA binding

Journal of Molecular Liquids, Journal Year: 2024, Volume and Issue: 407, P. 125218 - 125218

Published: June 7, 2024

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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Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimer's disease and neuroinflammation

RSC Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 13(6), P. 737 - 745

Published: Jan. 1, 2022

Mitogen-activated protein kinases (MAPKs) govern various cellular programs and crucial intermediate pathways in signaling. Microtubule affinity-regulating kinase 4 (MARK4) is a part of the family recognized for actively phosphorylating neural microtubule-associated proteins (MAPs) like MAP2, MAP4 most importantly, tau. The Ser/Thr MARK4 overexpression associated with life-threatening conditions such as neurodegenerative disorders, diabetic neuropathy, cancer. Functionally, correlated many important signaling cascades transcription factors contributing to neurodegeneration cancer onset progression. Serotonin key molecule regulating mood, stress, behavioral aspects. Low serotonin levels promote progression neurological psychotic which also consequence tau accumulation. being major contributor tau, leading its accumulation, tauopathy, targeted inhibition by serotonin. study deals using combined computational experimental studies. results presented this paper provide strong evidence direct physical binding recombinant subsequent activity. In addition, we have performed molecular docking, followed 100 ns MD simulations presence serotonin, estimate stability protein-ligand complex. Since potential drug target can be exploited design discovery here are interest may further Alzheimer's disease (AD) other diseases.

Language: Английский

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Investigating binding mechanism of thymoquinone to human transferrin, targeting Alzheimer's disease therapy

Journal of Cellular Biochemistry, Journal Year: 2022, Volume and Issue: 123(8), P. 1381 - 1393

Published: June 20, 2022

Abstract Iron deposition in the central nervous system (CNS) is one of causes neurodegenerative diseases. Human transferrin (hTf) acts as an iron carrier present blood plasma, preventing it from contributing to redox reactions. Plant compounds and their derivatives are frequently being used or delaying Alzheimer's disease (AD). Thymoquinone (TQ), a natural product has gained popularity because its broad therapeutic applications. TQ significant phytoconstituent Nigella sativa . The binding hTf was determined by spectroscopic methods isothermal titration calorimetry. We have observed that strongly binds with constant ( K ) 0.22 × 10 6 M −1 forming stable complex. In addition, calorimetry revealed spontaneous hTf. Molecular docking analysis showed key residues were involved TQ. further performed 250 ns molecular dynamics simulation which deciphered stability hTf‐TQ Structure suggested doesn't cause any alterations structure during course complex formed. Altogether, we elucidated mechanism hTf, can be implicated development novel strategy for AD therapy.

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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Integrated virtual screening and MD simulation study to discover potential inhibitors of Lyn-kinase: targeting cancer therapy

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: 41(20), P. 10558 - 10568

Published: Dec. 10, 2022

Tyrosine-protein kinase Lyn (LynK) has emerged as one of the most attractive therapeutic targets for cancer and diabetes. In this study, we used a multistep virtual screening process natural compounds to discover potential inhibitors LynK from IMPPAT database. The primary filters were based on Lipinski rules, ADMET properties, PAINS patterns. Then, binding affinities interaction analyses carried out high-affinity selectivity towards LynK. Eventually, two compounds, Glabrene Lactupicrin, identified with high affinity specificity LynK-binding pocket. Both exhibited drug-like predicted by analysis physicochemical parameters. molecular dynamics (MD) simulation study revealed that these bind ATP-binding pocket interact functionally significant residues stability without inducing any structural changes protein. Ultimately, may be regarded promising can lead molecules in drug development against LynK-related diseases.Communicated Ramaswamy H. Sarma

Language: Английский

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Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 2, 2022

Cinnamomum zeylanicum is a tropical plant with traditional medicinal significance that possesses antimicrobial, antifungal, anti-parasitic, and anti-tumor properties. Here, we have elucidated the effects of extract (CZE) its bioactive compound cinnamaldehyde (CIN) on oral cancer underlying molecular mechanisms. Anti-tumor activities CZE CIN were demonstrated by various in vitro experiments cells (SCC-4, SCC-9, SCC-25). The cell proliferation, growth, cycle arrest, apoptosis, autophagy analyzed MTT, clonogenic assay, propidium iodide, annexin-V-PI, DAPI, acridine orange staining, respectively. binding affinity towards dihydrofolate reductase p38-MAP kinase alpha was docking. Western blot assay performed to assess alteration expression proteins. treatment significantly inhibited growth proliferation dose-dependent manner. These treatments further induced autophagy. invasion cytoplasmic translocation NF-κB these lines. showed high MAP P38 affinities -6.8 -5.9 kcal/mol, decreased PI3k-AKT-mTOR pathways related VEGF, COX-2, Bcl-2, NF-κB, proteins post-treatment.

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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