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 Meroueh

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

Small Molecule Libraries
Ligands
Molecules
Urokinase-Type Plasminogen Activator
Dermatoglyphics
Proteins
Sulfhydryl Compounds
Inhibitory Concentration 50
Oxidation-Reduction

Keywords

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

ASJC Scopus subject areas

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

Cite this

Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small-Molecule Antagonists. / Xu, David; Bum-Erdene, Khuchtumur; Si, Yubing; Zhou, Donghui; Ghozayel, Mona K.; Meroueh, Samy.

In: ChemMedChem, Vol. 12, No. 21, 08.11.2017, p. 1794-1809.

Research output: Contribution to journalArticle

Xu, David ; Bum-Erdene, Khuchtumur ; Si, Yubing ; Zhou, Donghui ; Ghozayel, Mona K. ; Meroueh, Samy. / Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small-Molecule Antagonists. In: ChemMedChem. 2017 ; Vol. 12, No. 21. pp. 1794-1809.
@article{3e49aa0a79f648daad00dfe7e0b0d7ff,
title = "Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small-Molecule Antagonists",
abstract = "Tight protein–protein interactions (Kd<100 nm) that occur over a large binding interface (>1000 {\AA}2) 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.",
keywords = "protein–protein interactions, small molecules, urokinase receptor, virtual screening",
author = "David Xu and Khuchtumur Bum-Erdene and Yubing Si and Donghui Zhou and Ghozayel, {Mona K.} and Samy Meroueh",
year = "2017",
month = "11",
day = "8",
doi = "10.1002/cmdc.201700572",
language = "English (US)",
volume = "12",
pages = "1794--1809",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "21",

}

TY - JOUR

T1 - Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small-Molecule Antagonists

AU - Xu, David

AU - Bum-Erdene, Khuchtumur

AU - Si, Yubing

AU - Zhou, Donghui

AU - Ghozayel, Mona K.

AU - Meroueh, Samy

PY - 2017/11/8

Y1 - 2017/11/8

N2 - 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.

AB - 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.

KW - protein–protein interactions

KW - small molecules

KW - urokinase receptor

KW - virtual screening

UR - http://www.scopus.com/inward/record.url?scp=85033496524&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033496524&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201700572

DO - 10.1002/cmdc.201700572

M3 - Article

C2 - 28960868

AN - SCOPUS:85033496524

VL - 12

SP - 1794

EP - 1809

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 21

ER -