Cited by 109Computational Drug Discovery MethodsChemical Synthesis and AnalysisProtein Degradation and Inhibitors

Targeting Protein–Protein Interactions and Fragment-Based Drug Discovery

Valkov, Eugene, Sharpe, Tim, Marsh, May, Greive, Sandra, Hyvönen, Marko·2011·Topics in Current Chemistry

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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Crossref · 10.1007/128_2011_265

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204 of 204 references verified0 citation errors · 0 not checkable

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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
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
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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