Structure-Based Design of Potent Selective Nanomolar Type-II Inhibitors of Glycogen Synthase Kinase-3β

Matthew P Davies, Rocio Benitz, Concepcion Perez, Sven Jakupovic, PHILIP WELSBY, Klaudia Rzepecka, Jane Alder, Colin Davidson, Ana Martinez, Joseph M Hayes*

*Corresponding author for this work

    Research output: Contribution to journalArticle (journal)peer-review

    10 Citations (Scopus)
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    For the first time, the in silico design, screening, and in vitro validation of potent GSK-3β type-II inhibitors are presented. In the absence of crystallographic evidence for a DFG-out GSK-3β activation loop conformation, computational models were designed using an adapted DOLPHIN approach and a method consisting of Prime loop refinement, induced-fit docking, and molecular dynamics. Virtual screening of the Biogenics subset from the ZINC database led to an initial selection of 20 Phase I compounds revealing two low micromolar inhibitors in an isolated enzyme assay. Twenty more analogues (Phase II compounds) related to the hit [pyrimidin-2-yl]amino–furo[3,2-b]furyl–urea scaffold were selected for structure–activity relationship analysis. The Phase II studies led to five highly potent nanomolar inhibitors, with compound 23 (IC50 =0.087 μM) > 100 times more potent than the best Phase I inhibitor, and selectivity for GSK-3β inhibition compared to homologous kinases was observed. Ex vivo experiments (SH-SY5Y cell lines) for tau hyperphosphorylation revealed promising neuroprotective effects at low micromolar concentrations. The type-II inhibitor design has been unraveled as a potential route toward more clinically effective GSK-3β inhibitors.
    Original languageEnglish
    Pages (from-to)1497–1509
    Number of pages12
    JournalJournal of Medicinal Chemistry
    Issue number3
    Early online date27 Jan 2021
    Publication statusPublished - 11 Feb 2021


    • Alzheimer’s disease
    • DFG-out
    • kinase
    • loop prediction
    • type-II inhibitors


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