Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists.

ABSTRACT: Tight protein-protein interactions (K_d <100 nm) that occur over a large binding interface (>1000 Ų ) are highly challenging to disrupt with small molecules. Historically, the design of small molecules to inhibit protein-protein interactions has focused on mimicking the position of interface protein ligand side chains. Here, we explore mimicry of the pairwise intermolecular interactions of the native protein ligand with residues of the protein receptor to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions. We use the high-affinity interaction (K_d =1 nm) between the urokinase receptor (uPAR) and its ligand urokinase (uPA) to test our methods. We introduce three methods for rank-ordering small molecules docked to u

SUBMITTER: Xu D 

PROVIDER: S-EPMC6067920 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature