2. Academic Validation
  3. Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

  • ACS Pharmacol Transl Sci. 2024 Mar 21;7(4):1086-1100. doi: 10.1021/acsptsci.3c00378.
Shannon T Smith 1,  Jackson B Cassada 2,  Lukas Von Bredow 3 4,  Kevin Erreger 2,  Emma M Webb 2,  Trevor A Trombley 3,  Jacob J Kalbfleisch 1 3,  Brian J Bender 5,  Irene Zagol-Ikapitte 3,  Valerie M Kramlinger 2 3,  Jacob L Bouchard 3,  Sidnee G Mitchell 2,  Maik Tretbar 4,  Brian K Shoichet 5,  Craig W Lindsley 2 1 3,  Jens Meiler 2 1 4,  Heidi E Hamm 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 3 Warren Center for Neuroscience Drug Discovery, Nashville, Tennessee 37067, United States.
  • 4 Institute for Drug Discovery, Leipzig University Medical School, Leipzig 04109, Germany.
  • 5 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States.
PMID: 38633591 DOI: 10.1021/acsptsci.3c00378
Abstract

Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using a homology model of a difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated Receptor 4 (PAR4) is activated by Thrombin cleavage, revealing a tethered ligand that activates the receptor, making PAR4 a challenging target. A virtual screen of a make-on-demand chemical library yielded a one-hit compound. From the single-hit compound, we developed a novel series of PAR4 antagonists. Subsequent lead optimization via simultaneous virtual library searches and structure-based rational design efforts led to potent antagonists of thrombin-induced activation. Interestingly, this series of antagonists was active against PAR4 activation by the native protease Thrombin cleavage but not the synthetic PAR4 Agonist peptide AYPGKF.

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