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Cited by 6Wnt/β-catenin signaling in development and cancerComputational Drug Discovery MethodsReceptor Mechanisms and Signaling

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In silico docking yields small molecule negative allosteric modulators targeting the core of Frizzled 7

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Scharf, Magdalena M., Kinsolving, Julia, Grätz, Lukas, Voss, Jan Hendrik, Carrasco-Busturia, David, Forsberg, Björn, Kolb, Peter, Schulte, Gunnar·2025·Nature Communications
DOI 10.1038/s41467-025-67147-zPMC PMC12705740

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Abstract

Targeting the Frizzled family (FZD 1-10 ) of WNT receptors pharmacologically has, despite substantial therapeutic potential, proven difficult. Given an almost complete lack of validated, effective small molecules targeting FZDs, no putative ligand binding site has so far been identified. In order to target FZD 7 , a potential target for the treatment of intestinal tumors, we combine an approach of adapted docking setups and large molecular library docking screens, identifying compound C407. Applying pharmacological assays, genetically-encoded biosensors, site-directed mutagenesis, cryo-electron microscopy and molecular dynamics simulations, the compound binding site in the core of the seven transmembrane bundle is validated and C407 is confirmed as a negative allosteric modulator of WNT-induced and FZD-mediated WNT/ β -catenin signaling. In summary, we provide here the proof-of-principle that targeting FZDs with small molecule compounds is possible and effective. Future hit optimization and functional validation in disease-relevant in vitro and in vivo models will pave the way towards clinical exploration.

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Metadata

Authors
Scharf, M. M., Kinsolving, J., Grätz, L., Voss, J. H., Carrasco-Busturia, D., Forsberg, B., Kolb, P., & Schulte, G.
Affiliations
  • Karolinska Institutet (SE)
  • University of Bonn (DE)
  • Linköping University (SE)
  • Philipps University of Marburg (DE)
Corresponding author
Schulte, Gunnar
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-12-14
Volume
16
Issue
1
Pages
11138-11138
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-67147-z
PMC
PMC12705740
OpenAlex
W4417303264
Cited by
6
References
1
Citations by year
2026: 6
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (101199012, 2020 ‘)
  • Deutsche Forschungsgemeinschaft (520506488, 470002134, 504098926)
  • Cancerfonden (NNF22OC0078104, 23 2825 Pj, 20 1102 PjF, 2017/561, 2019-, CAN2017/561)
  • Svenska Sällskapet för Medicinsk Forskning (PG-22-0379)
  • Karolinska Institutet
  • Knut och Alice Wallenbergs Stiftelse (KAW 2020.0239)
  • Novo Nordisk
  • Vetenskapsrådet (2019-01190, 01190, 2017-04676, 2024-02515, 2022-06725)
  • Science for Life Laboratory (KAW 2020.0239)
  • Novo Nordisk Fonden (NNF22OC0078104, NNF21OC0070008)
  • HORIZON EUROPE Framework Programme
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
Frizzled-7, Wnt receptors, negative allosteric modulators, small-molecule ligands, Wnt/β-catenin signaling, ligand binding sites, intestinal tumors, genetically encoded biosensors, molecular docking
MeSH terms
Allosteric Regulation, Binding Sites, Humans, Ligands, Mutagenesis, Site-Directed, Cryoelectron Microscopy, Frizzled Receptors, beta Catenin, Small Molecule Libraries, Molecular Dynamics Simulation, HEK293 Cells, Wnt Signaling Pathway, Molecular Docking Simulation

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