Cited by 72Computational Drug Discovery MethodsProtein Structure and DynamicsEnzyme Structure and Function

Modulating Protein–Protein Interactions with Small Molecules: The Importance of Binding Hotspots

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Thangudu, Ratna Rajesh, Bryant, Stephen H., Panchenko, Anna R., Madej, Thomas·2012·Journal of Molecular Biology

Abstract

The modulation of protein-protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes, it is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein-protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein-protein binding and discuss examples of new candidates for drug design.

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Authors
Thangudu, R. R., Bryant, S. H., Panchenko, A. R., & Madej, T.
Affiliations
National Institutes of Health (US)
Corresponding author
  • Panchenko, Anna R.
  • Madej, Thomas
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2012-01
Volume
415
Issue
2
Pages
443-453
ISSN
0022-2836 (ISSN-L)
OpenAlex
W2044199868
Cited by
71
References
60
Citations by year
2026: 6 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 6 · 2013: 11 · 2012: 2
FWCI
5.73
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health/Department of Health and Human Services
  • Intramural Research Program of the National Library of Medicine
Topics
  • 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
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
protein-protein interaction, small molecule modulators, binding hot spots, protein complexes, transient protein complexes, drug target identification, PPI inhibitors
MeSH terms
Binding Sites, Computer Simulation, Drug Evaluation, Preclinical, Models, Molecular, Protein Binding, Proteins, Protein Interaction Domains and Motifs, Drug Discovery

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