Reaching for high-hanging fruit in drug discovery at protein–protein interfaces

  title={Reaching for high-hanging fruit in drug discovery at protein–protein interfaces},
  author={James A. Wells and Christopher L. McClendon},
Targeting the interfaces between proteins has huge therapeutic potential, but discovering small-molecule drugs that disrupt protein–protein interactions is an enormous challenge. Several recent success stories, however, indicate that protein–protein interfaces might be more tractable than has been thought. These studies discovered small molecules that bind with drug-like potencies to 'hotspots' on the contact surfaces involved in protein–protein interactions. Remarkably, these small molecules… 

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.

Oncogenic protein interfaces: small molecules, big challenges

Some of the latest techniques to discover modulators of protein–protein interactions are described and how current drug discovery approaches have been adapted to successfully target these interfaces are described.

Wrapping mimicking in drug‐like small molecules disruptive of protein–protein interfaces

By revealing the replacement the small molecule performs of relevant wrapping interactions of protein–protein associations, this work conveys precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug‐design endeavors.

Protein–protein interactions as targets for small-molecule therapeutics in cancer

This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein-protein interactions that have therapeutic potential for cancer.

Targeting protein-protein interaction by small molecules.

This article reviews some of the recent advances in the discovery of small-molecule regulators of PPIs that involve key oncogenic proteins and focuses on the three key modes of action: orthosteric inhibition, allosteric regulation, and interfacial binding/stabilization.

Hot spots in protein-protein interfaces: towards drug discovery.

Targeting protein-protein interactions and fragment-based drug discovery.

Recent developments in the field of PPI inhibition are reviewed, with emphasis on fragment-based methods, and various factors one should take into account when developing small molecule inhibitors targeted at PPI interfaces are discussed.

Modulating protein-protein interactions: the potential of peptides.

This review will focus on the latest progress in the field of peptide drugs and homologous compounds, spanning from "lead" identification methods to binding evaluation techniques, through an update of the most successful examples described in the literature.



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

Here, illustrative examples are used to discuss general strategies for addressing the challenges inherent in the discovery and characterization of small-molecule inhibitors of protein–protein interactions.

Protein-protein interactions and cancer: small molecules going in for the kill.

  • M. Arkin
  • Biology, Chemistry
    Current opinion in chemical biology
  • 2005

Protein-protein interactions as targets for small molecule drug discovery.

  • D. Fry
  • Biology, Chemistry
  • 2006
The structural characteristics of the protein binding sites and the attributes of the small molecule ligands are focused upon, in an attempt to derive commonly shared principles that may be of general usefulness in future drug discovery efforts within this target class.

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.

Effects of Conformational Dynamics on Predicted Protein Druggability

To investigate the influence of a protein’s conformational flexibility on its druggability assessment, MD simulations on three proteins are reported, and how inherent receptor flexibility and the accompanying dynamic fluctuations influence predicted pocket Druggability is investigated.

Binding of small molecules to an adaptive protein–protein interface

  • M. ArkinM. Randal A. Braisted
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
The adaptive nature of a protein–protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.

Structure-based maximal affinity model predicts small-molecule druggability

It is shown that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site and that these calculated values correlate with drug discovery outcomes.

Inhibition of protein–protein interactions: The discovery of druglike β‐catenin inhibitors by combining virtual and biophysical screening

The interaction between β‐catenin and Tcf family members is crucial for the Wnt signal transduction pathway, which is commonly mutated in cancer, and inhibiting such interactions using low molecular weight inhibitors is a challenge.

Hot-spot mimicry of a cytokine receptor by a small molecule

The studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots.

The protein network as a tool for finding novel drug targets.

  • Michael StrongD. Eisenberg
  • Biology
    Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques
  • 2007
Methods for the identification and analysis of genome-wide protein networks are discussed, and how protein networks can be used to aid the identification of novel drug targets are discussed.