Small-molecule inhibitors of protein–protein interactions: progressing towards the dream

@article{Arkin2004SmallmoleculeIO,
  title={Small-molecule inhibitors of protein–protein interactions: progressing towards the dream},
  author={Michelle R. Arkin and James A. Wells},
  journal={Nature Reviews Drug Discovery},
  year={2004},
  volume={3},
  pages={301-317}
}
  • M. ArkinJ. Wells
  • Published 1 April 2004
  • Biology, Chemistry
  • Nature Reviews Drug Discovery
Protein–protein interactions have a key role in most biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein–protein interactions is difficult, owing to issues such as the lack of well-defined binding pockets. Nevertheless, there has been important progress in this endeavour in recent years. Here, we use illustrative examples to discuss general strategies for addressing the challenges inherent in the discovery and… 

Inhibiting protein-protein interactions using designed molecules.

Rational design of protein–protein interaction inhibitors

This review highlights the very recent developments in the rational design of protein–protein interaction inhibitors, which have recently reached clinical trials.

Strategies for targeting protein-protein interactions with synthetic agents.

This review discusses the strategies for targeting protein-protein interactions and the state of the art in the rational design of molecules that mimic the structures and functions of their natural targets.

Development of small molecules designed to modulate protein–protein interactions

A general approach is described based on the “privileged-structure hypothesis” – that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists – to address the challenges inherent in the discovery of small-molecule inhibitors of protein–protein interactions.

Overview of Protein-Protein Interactions and Small-Molecule Inhibitors Under Clinical Development

This chapter aims to give an overview of the structural features of PPIs as well as the design strategies of small-molecule PPI inhibitors.

Targeting protein-protein interactions for drug discovery.

  • D. Fry
  • Biology, Chemistry
    Methods in molecular biology
  • 2015
These experiences are starting to provide general strategies and tools to help overcome the problems inherent in pursuing protein-protein interaction targets and should improve the rate of success as these systems are pursued in the future.

Emerging classes of protein-protein interaction inhibitors and new tools for their development.

Protein-Protein Interaction Inhibitors: Case Studies on Small Molecules and Natural Compounds

Many biological functions involve the formation of protein–protein complexes, and the inhibition of this process has garnered significant interest in pharmaceutical research investigating novel

Prospects of Modulating Protein–Protein Interactions

This chapter provides an overview of the approaches used for the design of chemical modulators of protein–protein interactions using computational methods in combination with experimental assays.

Small Molecule Protein–Protein Interaction Inhibitors as CNS Therapeutic Agents: Current Progress and Future Hurdles

Recent work towards developing small molecule inhibitors of amyloid-β and α-synuclein aggregation, inhibitors of critical components of G-protein-signaling pathways, and PDZ domain inhibitors are focused upon.
...

References

SHOWING 1-10 OF 184 REFERENCES

Inhibitors of protein-protein interactions

Examples are presented of currently marketed drugs, compounds in clinical development and lead molecules in research programmes, which have been identified as inhibitors of protein-protein interactions.

Small molecule antagonists of proteins.

Protein-protein interactions: lessons learned.

This review examines P-P interactions with particular emphasis on the discovery of new anti-tumor drugs, including underlying physical forces that determine affinity and specificity and discusses classical and newer strategies used to discover inhibitors of P-p interactions.

Modulation of protein-protein interactions with small organic molecules.

  • T. Berg
  • Biology, Chemistry
    Angewandte Chemie
  • 2003
A number of protein-protein interactions that are considered to be pharmaceutical targets are presented, which will familiarize the reader with the strategies that have been employed for the successful identification of small molecule modulators of these protein- protein interactions.

Protein-protein interfaces: mimics and inhibitors.

  • A. Cochran
  • Biology, Chemistry
    Current opinion in chemical biology
  • 2001

A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors.

A novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches, is presented, which successfully used the basis for structure-activity relationships of previously selected small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.

Implications of protein flexibility for drug discovery

  • S. Teague
  • Biology, Chemistry
    Nature Reviews Drug Discovery
  • 2003
This work has shown that protein flexibility allows increased affinity to be achieved between a drug and its target, crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.

Discovery of a potent small molecule IL-2 inhibitor through fragment assembly.

Using a site-directed fragment discovery method called tethering, a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Ralpha) with cell-based activity is identified and represents the highest affinity inhibitor reported against this protein-protein target class.
...