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Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

Seungkirl Ahn1, Alem W Kahsai1, Biswaranjan Pani1

  • 1Department of Medicine, Duke University Medical Center, Durham, NC 27710.

Proceedings of the National Academy of Sciences of the United States of America
|January 29, 2017
PubMed
Summary

Researchers discovered a novel small molecule, compound 15, that acts as a negative allosteric modulator for the beta-2 adrenergic receptor (β2AR). This finding opens new avenues for developing targeted G-protein-coupled receptor (GPCR) drugs with unique allosteric mechanisms.

Keywords:
DNA-encoded small-molecule libraryG-protein–coupled receptorallosteric modulatordrug discoveryβ2-adrenergic receptor

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Discovery

Background:

  • The beta-2 adrenergic receptor (β2AR), a G-protein-coupled receptor (GPCR), is crucial in cardiovascular and pulmonary functions.
  • Current β2AR drugs target the orthosteric site, limiting therapeutic options.

Purpose of the Study:

  • To discover allosteric ligands for the β2AR using DNA-encoded small-molecule libraries.
  • To characterize the novel allosteric modulator's mechanism and effects.

Main Methods:

  • Screening of 190 million DNA-encoded compounds against purified human β2AR.
  • Characterization of compound 15's binding affinity and allosteric modulation.
  • Cell-based signaling assays measuring cAMP production and β-arrestin recruitment.

Main Results:

  • Discovery of compound 15, a novel negative allosteric modulator with low micromolar affinity for β2AR.
  • Compound 15 enhances inverse agonist binding and inhibits agonist binding.
  • Compound 15 inhibits β2AR-mediated cAMP production and β-arrestin recruitment.

Conclusions:

  • Compound 15 represents a first-in-class allosteric small-molecule ligand for the β2AR.
  • The DNA-encoded library screening approach is effective for GPCR drug discovery.
  • This method facilitates the development of GPCR drugs with tailored allosteric effects.