Dickkopf-1 (DKK1) mediated dysregulation of the Wnt/β-catenin signaling pathway contributes to synaptic loss in Alzheimer's disease (AD). Risedronate, a third-generation bisphosphonate, shows promise in pathologies related to the Wnt pathway, although its direct interaction with the DKK1-LRP6 complex has yet to be investigated. This study aimed to characterize risedronate as a novel small-molecule DKK1 antagonist and evaluate its capacity to restore canonical Wnt signaling and provide neuroprotection. In silico studies were performed using the Schrödinger Maestro (v2018-3) platform, utilizing molecular docking, molecular simualtion, SiteMap and WaterMap analysis to define the thermodynamic hydration energetics of the DKK1-LRP6 interface. In vitro validation was conducted using LRP6-overexpressing HEK-293T cells, with Wnt modulation quantified via immunofluorescence of membrane-associated DKK1 and β-catenin stabilization assays and neuroprotective assay in presence of glutamate in SHSY5Y cells. In silico analysis identified a high-affinity binding site on the DKK1 C-terminal domain (Dscore: 0.998). WaterMap analysis and simulation study revealed that risedronate binding is driven by the displacement of high-energy "unfavorable" water molecules (ΔG > 0) at the Arg203/Lys222 residue cluster. In HEK-293LRP6 cells, risedronate (IC 50 : 65.94 μM) significantly attenuated DKK1-mediated LRP6 sequestration (p 0).o Wnt Pathway Restoration: Risedronate competitively inhibits the DKK1-LRP6 interaction, effectively restoring the canonical Wnt signaling flux. • Risedronate was identified as a novel small-molecule antagonist of DKK1 • In silico docking shows risedronate binds the DKK1-LRP6 interaction interface • MD simulations confirmed the structural stability of the risedronate-DKK1 complex • Risedronate restores Wnt signaling in LRP6-overexpressing HEK-293 cells • Risedronate exhibits potent neuroprotective effects by modulating the Wnt pathway.
Manandhar et al. (Fri,) studied this question.