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

Davies, Matthew P, Benitez, Rocio, Perez, Concepcion, Jakupovic, Sven, Welsby, Philip John orcid iconORCID: 0000-0002-2110-8198, Rzepecka, Klaudia Magdalena, Alder, Jane Elizabeth orcid iconORCID: 0000-0003-4463-0349, Davidson, Colin orcid iconORCID: 0000-0002-8180-7943, Martinez, Ana et al (2021) Structure-Based Design of Potent Selective Nanomolar Type-II Inhibitors of Glycogen Synthase Kinase-3β. Journal of Medicinal Chemistry, 64 (3). pp. 1497-1509. ISSN 0022-2623

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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.

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