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

Molecules

Benjamin P. Cossins¹  Alastair D. G. Lawson² 

[1] Computer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UK; E-Mail

关键词: protein–protein interaction;    allosteric;    protein dynamics;    small molecule;   

DOI  :  10.3390/molecules200916435

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.