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.

A simple and efficient method has been developed for the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) by the condensation reaction between substituted aldehydes, and 1-phenyl-3-methylpyrazol-5-one in the presence of xanthan sulfuric acid (XSA) as a solid acid catalyst. This method is simple and cost-effective with short reaction times. Yields are excellent with high purity, and the catalyst could be easily recycled.

A series of novel hybrid 8-hydroxyquinoline-indole derivatives (7a–7e, 12a–12b and 18a–18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ_1–42 aggregation as potential treatments for Alzheimer’s disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ_1–42 aggregation as 18c, 18d and 18f (EC₅₀ = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (1, EC₅₀ = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ_1–42 aggregation in the presence of Cu²⁺ or Zn²⁺ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu²⁺- induced and Zn²⁺- induced Aβ_1–42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP_Sw cells. Molecular docking studies with the most active compounds performed against Aβ_1–42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π–π stacking interactions and π–cation interactions with Aβ_1–42, which may inhibit both self-aggregation as well as metal ion binding to Aβ_1–42 to favor the inhibition of Aβ_1–42 aggregation.