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

5 years ago

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

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

Tight protein-protein interactions (Kd < 100 nM) that occur over a large binding interface (> 1,000 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 sidechains. 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 interaction (Kd = 1 nM) between the urokinase receptor (uPAR) and its ligand urokinase (uPA). We introduce three methods for rank-ordering small molecules docked to uPAR: (i) a new fingerprint approach that represents uPA's pairwise interaction energies with uPAR residues; (ii) a pharmacophore approach to identify small molecules that mimic the position of uPA interface residues; and (iii) a combined fingerprint and pharmacophore approach. Our work led to small molecules with novel chemotypes that inhibited a tight uPAR*uPA interaction with single-digit micromolar IC50s. 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700572