Modulating Protein–Protein Interactions with Small Molecules: The Importance of Binding Hotspots
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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)
- PMC
- PMC3433052
- 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
- hybrid
- doi.org
- Licence
- 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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