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

David Xu, Khuchtumur Bum-Erdene, Yubing Si, Donghui Zhou, Mona K. Ghozayel, Samy O. Meroueh

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Tight protein–protein interactions (Kd<100 nm) that occur over a large binding interface (>1000 Å2) 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 (Kd=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 uPAR: 1) a new fingerprint approach that represents uPA′s pairwise interaction energies with uPAR residues; 2) a pharmacophore approach to identify small molecules that mimic the position of uPA interface residues; and 3) a combined fingerprint and pharmacophore approach. Our work led to small molecules with novel chemotypes that inhibited a tight uPAR⋅uPA protein–protein interaction with single-digit micromolar IC50 values. We also report the extensive work that identified several of the hits as either lacking stability, thiol reactive, or redox active. This work suggests that mimicking the binding profile of the native ligand and the position of interface residues can be an effective strategy to enrich commercial libraries for small-molecule inhibitors of tight protein–protein interactions.

Original languageEnglish (US)
Pages (from-to)1794-1809
Number of pages16
JournalChemMedChem
Volume12
Issue number21
DOIs
StatePublished - Nov 8 2017

Keywords

  • protein–protein interactions
  • small molecules
  • urokinase receptor
  • virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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