{"doi":"10.1021/acsptsci.3c00378","title":"Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening","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.","journal":"ACS Pharmacology & Translational Science","year":2024,"id":435003,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1242720,"name":"Jackson B. Cassada","orcid":null,"position":1,"is_corresponding":false},{"id":1225113,"name":"Lukas von Bredow","orcid":"0009-0009-5021-7711","position":2,"is_corresponding":false},{"id":574477,"name":"Kevin Erreger","orcid":"0000-0001-5801-2344","position":3,"is_corresponding":false},{"id":1242163,"name":"Emma M. Webb","orcid":"0000-0002-0281-3326","position":4,"is_corresponding":false},{"id":1242164,"name":"Trevor A. Trombley","orcid":"0000-0003-0413-0913","position":5,"is_corresponding":false},{"id":898026,"name":"Jacob J. Kalbfleisch","orcid":null,"position":6,"is_corresponding":false},{"id":357084,"name":"Brian J. Bender","orcid":"0000-0001-9251-9480","position":7,"is_corresponding":false},{"id":346380,"name":"Irène Zagol-Ikapitte","orcid":null,"position":8,"is_corresponding":false},{"id":1242165,"name":"Valerie M. Kramlinger","orcid":"0000-0002-7237-164X","position":9,"is_corresponding":false},{"id":792203,"name":"Jacob L. Bouchard","orcid":"0000-0002-5936-1244","position":10,"is_corresponding":false},{"id":794537,"name":"Sidnee G. Mitchell","orcid":null,"position":11,"is_corresponding":false},{"id":1242166,"name":"Maik Tretbar","orcid":"0000-0003-3819-7358","position":12,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":13,"is_corresponding":false},{"id":352918,"name":"Craig W. Lindsley","orcid":"0000-0003-0168-1445","position":14,"is_corresponding":false},{"id":36757,"name":"Jens Meiler","orcid":"0000-0001-8945-193X","position":15,"is_corresponding":false},{"id":511533,"name":"Heidi E. Hamm","orcid":"0000-0001-5437-5287","position":16,"is_corresponding":false},{"id":470289,"name":"Shannon T. Smith","orcid":"0000-0002-1225-8928","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:00:03.406367Z","pmid":"38633591","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}