title: Small Molecule Targeting of Protein-Protein Interactions through Allosteric Modulation of Dynamics.
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.
authors.affiliation: Computer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UK. Ben.Cossins@ucb.com.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Cossins
authors.affiliation: Computer-Aided Drug Design and Structural Biology, UCB, 216 Bath Road, Slough, SL1 3WE, UK. alastair.lawson@ucb.com.
authors.forename: Alastair D G
authors.initials: AD
authors.lastname: Lawson
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries
keywords: allosteric; protein dynamics; protein–protein interaction; small molecule