Cited by 121Chemical Synthesis and AnalysisComputational Drug Discovery MethodsProtein Degradation and Inhibitors

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Ni, Duan, Lu, Shaoyong, Zhang, Jian·2019·Medicinal Research Reviews

Abstract

Protein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.

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Crossref · 10.1002/med.21585

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Authors
Ni, D., Lu, S., & Zhang, J.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Lu, Shaoyong
  • Zhang, Jian
Venue
Medicinal Research Reviews
Publisher
Wiley
Published
2019-04-07
Volume
39
Issue
6
Pages
2314-2342
ISSN
  • 0198-6325 (ISSN-L)
  • 1098-1128
OpenAlex
W2939052792
Cited by
116
References
227
Citations by year
2026: 10 · 2025: 15 · 2024: 13 · 2023: 17 · 2022: 18 · 2021: 18 · 2020: 16 · 2019: 8
FWCI
1.39
Type
journal article
Language
en
Open access
closed
Locations
  • Medicinal Research Reviews (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (91753117, 81473137, 81322046, 21778037, 81603023)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
protein-protein interaction, allosteric modulators, allosteric regulation, PPI inhibitors, undruggable targets, allosteric site, computer-aided drug design
MeSH terms
Allosteric Regulation, Allosteric Site, Animals, Humans, Protein Binding, GTP-Binding Proteins, Protein Interaction Mapping, Drug Discovery

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