SPLINTS: Small-molecule Protein Ligand Interface Stabilizers

Overview

Journal Curr Opin Struct Biol

Date 2016 Feb 2

PMID 26829757

Citations 20

Authors

Eric S Fischer

Eunyoung Park

Michael J Eck

Nicolas H Thoma

Affiliations

Soon will be listed here.

Abstract

Regulatory protein-protein interactions are ubiquitous in biology, and small molecule protein-protein interaction inhibitors are an important focus in drug discovery. Remarkably little attention has been given to the opposite strategy-stabilization of protein-protein interactions, despite the fact that several well-known therapeutics act through this mechanism. From a structural perspective, we consider representative examples of small molecules that induce or stabilize the association of protein domains to inhibit, or alter, signaling for nuclear hormone, GTPase, kinase, phosphatase, and ubiquitin ligase pathways. These SPLINTS (small-molecule protein ligand interface stabilizers) drive interactions that are in some cases physiologically relevant, and in others entirely adventitious. The diverse structural mechanisms employed suggest approaches for a broader and systematic search for such compounds in drug discovery.

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