Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions
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The systematic stabilization of protein–protein interactions (PPI) has great potential as innovative drug discovery strategy to target novel and hard-to-drug protein classes. The current lack of chemical starting points and focused screening opportunities limits the identification of small molecule stabilizers that engage two proteins simultaneously. Starting from our previously described virtual screening strategy to identify inhibitors of 14-3-3 proteins, we report a conceptual molecular docking approach providing concrete entries for discovery and rational optimization of stabilizers for the interaction of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP). X-ray crystallography reveals a distinct difference in the binding modes between weak and general inhibitors of 14-3-3 complexes and a specific, potent stabilizer of the 14-3-3/ChREBP complex. Structure-guided stabilizer optimization results in selective, up to 26-fold enhancement of the 14-3-3/ChREBP interaction. This study demonstrates the potential of rational design approaches for the development of selective PPI stabilizers starting from weak, promiscuous PPI inhibitors.
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Recently, an optimization cycle guided by docking was able to evolve a promiscuous ligand of 14-3-3 proteins to a selective PPI inhibitor.
“Recently, an optimization cycle guided by docking was able to evolve a promiscuous ligand of 14–3–3 proteins to a selective PPI inhibitor.259”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [259]
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Self-citation
- Authors
- Sijbesma, E., Visser, E., Plitzko, K., Thiel, P., Milroy, L.-G., Kaiser, M., Brunsveld, L., & Ottmann, C.
- Affiliations
- Eindhoven University of Technology (NL)
- University of Duisburg-Essen (DE)
- University of Tübingen (DE)
- Corresponding author
- Kaiser, Markus
- Brunsveld, Luc
- Ottmann, Christian
- ORCID
- Venue
- Nature Communications
- Published
- 2020-08-07
- Volume
- 11
- Issue
- 1
- Pages
- 3954-3954
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7414219
- OpenAlex
- W3048218277
- Cited by
- 72
- References
- 48
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 13 · 2023: 13 · 2022: 9 · 2021: 9 · 2020: 1
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- TU/e Research Portal (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (CRC1093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- 14-3-3 proteins, ChREBP, PPI inhibitors, structure-based drug design, virtual screening, molecular docking, small molecule stabilizer
- MeSH terms
- Protein Binding, Structure-Activity Relationship, Drug Design, Crystallography, X-Ray, 14-3-3 Proteins, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Small Molecule Libraries, Drug Discovery, Molecular Docking Simulation
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