ArticleACS pharmacology & translational science2024
Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening.
Article in ACS pharmacology & translational science, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Automated Parallel Synthesis Accelerates Virtual Screening Hit Discovery.Journal of the American Chemical Society · 2026Article
- Neutrophil cathepsin G potentiates biased signaling through protease-activated receptor 4.Blood advances · 2026Article
- Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Demonstrate Thrombin Liability.ACS pharmacology & translational science · 2026Article
- Protease-activated receptor 4 deficiency increases mortality, intracranial bleeding, and blood-brain barrier impairment following traumatic brain injury in mice.Research and practice in thrombosis and haemostasis · 2025Article
- From theory to platelets: unraveling the history and complexities of biased signaling.Blood vessels, thrombosis & hemostasis · 2025Review
- Artificial Intelligence: A New Tool for Structure-Based G Protein-Coupled Receptor Drug Discovery.Biomolecules · 2025Review
- AI meets physics in computational structure-based drug discovery for GPCRs.npj drug discovery · 2025Review
- Development of a Divergent Synthesis Strategy for 5-Sulfonyl-Substituted Uracil Derivatives.The Journal of organic chemistry · 2024Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
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.
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.