Targeting Protein–Protein Interactions and Fragment-Based Drug Discovery
Abstract
Protein-protein interactions (PPI) are integral to the majority of biological functions. Targeting these interactions with small molecule inhibitors is of increased interest both in academia as well as in the pharmaceutical industry, both for therapeutic purposes and in the search for chemical tools for basic science. Although the number of well-characterised examples is still relatively modest, it is becoming apparent that many different kinds of interactions can be inhibited using drug-like small molecules. Compared to active site targeting, PPI inhibition suffers from the particular problem of more exposed and less defined binding sites, and this imposes significant experimental challenges to the development of PPI inhibitors. PPI interfaces are large, up to thousands of square angstroms, and there is still debate as to what part of the interface one should target. We will review recent developments in the field of PPI inhibition, with emphasis on fragment-based methods, and discuss various factors one should take into account when developing small molecule inhibitors targeted at PPI interfaces.
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- Authors
- Valkov, E., Sharpe, T., Marsh, M., Greive, S., & Hyvönen, M.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Hyvönen, Marko
- Venue
- Topics in Current Chemistry
- Publisher
- Springer Berlin Heidelberg
- Published
- 2011
- Volume
- 317
- Pages
- 145-179
- ISSN
- 0340-1022 (ISSN-L)
- 1436-5049
- OpenAlex
- W1506948354
- Cited by
- 107
- References
- 204
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 10 · 2015: 12 · 2014: 11 · 2013: 14 · 2012: 8
- FWCI
- 27.04
- Type
- book chapter
- Language
- en
- Open access
- closed
- Licence
- Locations
- Topics in current chemistry (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (submittedVersion)
- Funders
- Wellcome Trust (090340)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- protein-protein interaction, PPI inhibitors, fragment-based drug discovery, small molecule inhibitors, chemical probes
- MeSH terms
- Binding Sites, Protein Binding, Proteins, Structure-Activity Relationship, Small Molecule Libraries, Drug Discovery, Molecular Targeted Therapy, Protein Interaction Maps
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