ArticleBioinformatics and biology insights2023
A Novel Inhibitor of DKK1/LRP6 Interactions Against the Alzheimer Disease: An Insilco Approach.
Article in Bioinformatics and biology insights, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 11 citations in OpenAlex.
- Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.Current topics in medicinal chemistry · 2026Review
- A novel modulator of the Axin/β-Catenin interaction to restore EAAT2 expression in alzheimer's disease: an in-silico and in-vitro approach.Metabolic brain disease · 2025Article
- Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases.Molecular neurobiology · 2025Review
- Wnt/β-catenin Signaling in Central Nervous System Regeneration.Advances in experimental medicine and biology · 2025Review
- 3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists.Molecules (Basel, Switzerland) · 2024Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The activation of the Wnt signaling pathway is implicated in a neuroprotective mechanism against the Alzheimer disease. When this pathway is blocked, it activates GSK3 beta, leading to tau hyperphosphorylation and the apoptosis of neurons. Dickkopf-related protein 1 (DKK1) is a protein that competes with the Wnt ligand for the low-density lipoprotein receptor-related protein 6 (LRP6) receptor's binding, interrupting the Wnt-induced Fzd-Wnt-LRP6 complex. This counteracts Wnt's neuroprotective effect and contributes to the progression of the Alzheimer disease. The aim of this study was to use in silico approach to develop new agents that can combat the Alzheimer disease by targeting the interaction between DKK1 and LRP6. To achieve this, we conducted a virtual screening (Vsw) of the Asinex-CNS database library (n = 54 513) compounds against a generated grid in LRP6 protein. From this screening, we selected 6 compounds based on their docking score and performed molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations on the selected ligands. Next, we evaluated the Absorption, Distribution, Metabolism, and Excretion (ADME) results of the 6 screened compounds using the Quick prop module of Schrödinger. We then employed several computational techniques, including PCA (Principal Component Analysis), DCCM (Dynamic Cross-Correlation Map), molecular dynamics simulation, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA)-based negative binding free energy (BFE) calculation, to further analyze the compounds. Our extensive computational analysis resulted in the identification of 3 potential hits, LAS 29757582, LAS 29984441, and LAS 29757942. These compounds were found to block the interaction of DKK1 with LRP6 (A and B interface) protein, and their potential as therapeutic agents was supported by negative BFE calculation. Therefore, these compounds show potential as possible therapeutic agents for treating the Alzheimer disease through targeting the interaction between DKK1 and LRP6.
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