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

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 to conside...

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Bibliographic Details
Main Authors: Benjamin P. Cossins, Alastair D. G. Lawson
Format: Article
Language:English
Published: MDPI AG 2015-09-01
Series:Molecules
Subjects:
protein–protein interaction
allosteric
protein dynamics
small molecule
Online Access:http://www.mdpi.com/1420-3049/20/9/16435
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spelling doaj-5e2236397b7144a685b521e1971e3a8c2020-11-24T22:34:14ZengMDPI AGMolecules1420-30492015-09-01209164351644510.3390/molecules200916435molecules200916435Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of DynamicsBenjamin P. Cossins0Alastair D. G. Lawson1Computer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UKComputer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UKThe 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.http://www.mdpi.com/1420-3049/20/9/16435protein–protein interactionallostericprotein dynamicssmall molecule
collection DOAJ
language English
format Article
sources DOAJ
author Benjamin P. Cossins
Alastair D. G. Lawson
spellingShingle Benjamin P. Cossins
Alastair D. G. Lawson
Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
Molecules
protein–protein interaction
allosteric
protein dynamics
small molecule
author_facet Benjamin P. Cossins
Alastair D. G. Lawson
author_sort Benjamin P. Cossins
title Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
title_short Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
title_full Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
title_fullStr Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
title_full_unstemmed Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
title_sort small molecule targeting of protein–protein interactions through allosteric modulation of dynamics
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2015-09-01
description 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.
topic protein–protein interaction
allosteric
protein dynamics
small molecule
url http://www.mdpi.com/1420-3049/20/9/16435
work_keys_str_mv AT benjaminpcossins smallmoleculetargetingofproteinproteininteractionsthroughallostericmodulationofdynamics
AT alastairdglawson smallmoleculetargetingofproteinproteininteractionsthroughallostericmodulationofdynamics
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