title: Direct and Propagated Effects of Small Molecules on Protein-Protein Interaction Networks.
abstract: Networks of protein-protein interactions (PPIs) link all aspects of cellular biology. Dysfunction in the assembly or dynamics of PPI networks is a hallmark of human disease, and as such, there is growing interest in the discovery of small molecules that either promote or inhibit PPIs. PPIs were once considered undruggable because of their relatively large buried surface areas and difficult topologies. Despite these challenges, recent advances in chemical screening methodologies, combined with improvements in structural and computational biology have made some of these targets more tractable. In this review, we highlight developments that have opened the door to potent chemical modulators. We focus on how allostery is being used to produce surprisingly robust changes in PPIs, even for the most challenging targets. We also discuss how interfering with one PPI can propagate changes through the broader web of interactions. Through this analysis, it is becoming clear that a combination of direct and propagated effects on PPI networks is ultimately how small molecules re-shape biology.
authors.affiliation: Program in Chemical Biology, Life Sciences Institute, University of Michigan , Ann Arbor, MI , USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Cesa
authors.affiliation: Program in Chemical Biology, Life Sciences Institute, University of Michigan , Ann Arbor, MI , USA ; Department of Chemistry, University of Michigan , Ann Arbor, MI , USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Mapp
authors.affiliation: Program in Chemical Biology, Life Sciences Institute, University of Michigan , Ann Arbor, MI , USA ; Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Diseases, University of California San Francisco , San Francisco, CA , USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
keywords: PPI inhibition; allostery; multi-protein complexes