ArticleScientific reports2020
Structural modeling of GSK3β implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
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- Zolpidem restores sleep and decreases amyloid in a mouse model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
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- Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.Archives of toxicology · 2025Review
- Zolpidem restores sleep and slows Alzheimer's progression in a mouse model.bioRxiv : the preprint server for biology · 2025Article
- Integrative machine learning and molecular simulation approaches identify GSK3β inhibitors for neurodegenerative disease therapy.Scientific reports · 2025Article
- Structure and Dynamics of the ABL1 Tyrosine Kinase and Its Important Role in Chronic Myeloid Leukemia.Archiv der Pharmazie · 2025Review
- Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach.Scientific reports · 2025Article
- Dibenzo [a, c] phenazin-11-yl(phenyl) methanone (SBLJ23), a novel selective inhibitor targeting JAK2Oncology research · 2025Article
- The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.Frontiers in pharmacology · 2025Review
- Targeting the Inactive Conformation of the Epidermal Growth Factor Receptor Identifies EG31: A Novel Small Molecule Inhibitor Effective Against Normal and 5-Fluorouracil-Resistant Triple Negative Breast Cancer Cells.OncoTargets and therapy · 2025Article
- GSK3 inhibition improves skeletal muscle function and whole-body metabolism in male mouse models of Duchenne muscular dystrophy.Nature communications · 2024Article
- Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3β to Combat Alzheimer's Disease.Pharmaceutics · 2024Article
- C-5401331 identified as a novel T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) inhibitor to control acute myeloid leukemia (AML) cell proliferation.Medical oncology (Northwood, London, England) · 2024Article
- Alzheimer's-specific brain amyloid interactome: Neural-network analysis of intra-aggregate crosslinking identifies novel drug targets.iScience · 2024Article
- Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain.Cell death & disease · 2024Article
- Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer's disease by targeted small molecules.Communications biology · 2024Article
- Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease.Current topics in medicinal chemistry · 2024Article
- Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and ExtendPharmaceuticals (Basel, Switzerland) · 2023Article
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8 authors at 3 institutions in 1 country.
Funding
Abstract
Glycogen synthase kinase-3β (GSK3β) controls many physiological pathways, and is implicated in many diseases including Alzheimer's and several cancers. GSK3β-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3β protect against Alzheimer's disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3β with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3β, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3β. Our model predicts that phosphorylation of GSK3β Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3β to be inactive, and are consistent with biochemical evidence for the TDZD-8-interacting residues of GSK3β. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3β as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3β can facilitate the identification of novel GSK3β inhibitors of high potency and specificity.
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