Small Molecule Targeting of Protein-Protein Interactions through Allosteric Modulation of Dynamics

The protein-protein interaction (PPI) target class is particularly challenging, but offers potential for "first in class" therapies. Most known PPI small molecules are orthosteric inhibitors but many PPI sites may be fundamentally intractable to this approach. One potential alternative is...

Full description

Saved in:
Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2015-09, Vol.20 (9), p.16435-16445
Main Authors: Cossins, Benjamin P, Lawson, Alastair D G
Format: Article
Language:English
Subjects:
allosteric
Allosteric Regulation
Allosteric Site
Protein Binding
protein dynamics
Proteins - chemistry
protein–protein interaction
Review
small molecule
Small Molecule Libraries - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The protein-protein interaction (PPI) target class is particularly challenging, but offers potential for "first in class" therapies. Most known PPI small molecules are orthosteric inhibitors but many PPI sites may be fundamentally intractable to this approach. One potential alternative is to consider more attractive, remote small molecule pockets; however, on the whole, allostery is poorly understood and difficult to discover and develop. Here we review the literature in order to understand the basis for allostery, especially as it can apply to PPIs. We suggest that the upfront generation of sophisticated and experimentally validated dynamic models of target proteins can aid in target choice and strategy for allosteric intervention to produce the required functional effect.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules200916435