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Molecules 2015, 20(9), 16435-16445; doi:10.3390/molecules200916435

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

Computer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UK
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Author to whom correspondence should be addressed.
Academic Editor: Philippe Roche
Received: 7 August 2015 / Revised: 6 September 2015 / Accepted: 8 September 2015 / Published: 10 September 2015
(This article belongs to the Special Issue Small Molecules Modulation in Protein-Protein Interactions)
View Full-Text   |   Download PDF [667 KB, uploaded 10 September 2015]

Abstract

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. View Full-Text
Keywords: protein–protein interaction; allosteric; protein dynamics; small molecule protein–protein interaction; allosteric; protein dynamics; small molecule
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Cossins, B.P.; Lawson, A.D.G. Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics. Molecules 2015, 20, 16435-16445.

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