Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments

Pabla A. Barra, Verónica A. Jiménez, José A. Gavin, Antonio H. Daranas, Joel B. Alderete

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

E-selectin is an endothelial protein that participates in the adhesion of metastatic cancer cells, and is therefore a relevant target for antitumor therapeutic intervention. In this work, virtual screening was used to identify new E-selectin inhibitors from a subset of drug-like molecules retrieved from the ZINC database, including the physiological ligand sLex as reference structure (PDB ID: 1G1T). Four hits were chosen and subjected to molecular dynamics simulations and fluorescence binding assays, which led to the determination of experimental dissociation constants between 333 and 1012 μm. The candidate with the highest affinity was studied by saturation transfer difference (STD) NMR experiments and complete relaxation and conformational exchange matrix analysis of saturation transfer (CORCEMA-ST), aimed at identifying the preferable binding mode with E-selectin. Our results revealed that this new inhibitor binds more strongly than sLex in the E-selectin binding site, in good agreement with simulation predictions. These properties will prove valuable for the future design of drugs that target E-selectin.

Original languageEnglish
Pages (from-to)1008-1014
Number of pages7
JournalChemMedChem
Volume11
Issue number9
DOIs
Publication statusPublished - 6 May 2016

Fingerprint

E-Selectin
Assays
Screening
Fluorescence
Nuclear magnetic resonance
Experiments
Drug Design
Molecular Dynamics Simulation
Pharmaceutical Preparations
Molecular dynamics
Adhesion
Binding Sites
Cells
Databases
Ligands
Molecules
Computer simulation
Neoplasms
Proteins

Keywords

  • drug design
  • E-selectin
  • molecular dynamics
  • NMR spectroscopy
  • virtual screening

ASJC Scopus subject areas

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

Cite this

Barra, Pabla A. ; Jiménez, Verónica A. ; Gavin, José A. ; Daranas, Antonio H. ; Alderete, Joel B. / Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments. In: ChemMedChem. 2016 ; Vol. 11, No. 9. pp. 1008-1014.
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Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments. / Barra, Pabla A.; Jiménez, Verónica A.; Gavin, José A.; Daranas, Antonio H.; Alderete, Joel B.

In: ChemMedChem, Vol. 11, No. 9, 06.05.2016, p. 1008-1014.

Research output: Contribution to journalArticle

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