2. Academic Validation
  3. Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket

Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket

  • J Med Chem. 2021 Mar 11;64(5):2801-2814. doi: 10.1021/acs.jmedchem.0c02000.
Corinna Schüß 1,  Oanh Vu 2,  Mario Schubert 1,  Yu Du 3,  Nigam M Mishra 4,  Iain R Tough 5,  Jan Stichel 1,  C David Weaver 2 3 6,  Kyle A Emmitte 4,  Helen M Cox 5,  Jens Meiler 2 3 7,  Annette G Beck-Sickinger 1
Affiliations

Affiliations

  • 1 Institute of Biochemistry, Leipzig University, Leipzig 04103, Germany.
  • 2 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
  • 3 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States.
  • 5 King's College London, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, London SE1 1UL, U.K.
  • 6 Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 7 Institute for Drug Discovery, Leipzig University, Leipzig 04103, Germany.
PMID: 33595306 DOI: 10.1021/acs.jmedchem.0c02000
Abstract

Human neuropeptide Y receptors (Y1R, Y2R, Y4R, and Y5R) belong to the superfamily of G protein-coupled receptors and play an important role in the regulation of food intake and energy metabolism. We identified and characterized the first selective Y4R allosteric antagonist (S)-VU0637120, an important step toward validating Y receptors as therapeutic targets for metabolic diseases. To obtain insight into the antagonistic mechanism of (S)-VU0637120, we conducted a variety of in vitro, ex vivo, and in silico studies. These studies revealed that (S)-VU0637120 selectively inhibits native Y4R function and binds in an allosteric site located below the binding pocket of the endogenous ligand pancreatic polypeptide in the core of the Y4R transmembrane domains. Taken together, our studies provide a first-of-its-kind tool for probing Y4R function and improve the general understanding of allosteric modulation, ultimately contributing to the rational development of allosteric modulators for peptide-activated G protein-coupled receptors (GPCRs).

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