{"doi":"10.17615/9mzk-sp93","title":"Molecular Modeling of the Human P2Y2 Receptor and Design of a Selective Agonist, 2′-Amino-2′-deoxy-2-thio-UTP","abstract":"A rhodopsin-based homology model of the nucleotide-activated human P2Y2 receptor, including loops, termini, and phospholipids, was optimized with Monte Carlo Multiple Minimum. Docked UTP formed a nucleobase π–π complex with conserved Phe3.32. Selectivity-enhancing 2′-amino-2′-deoxy substitution interacted through π-hydrogen bonding with aromatic Phe6.51 and Tyr3.33. A “sequential ligand composition” approach for docking the flexible dinucleotide agonist Up4U demonstrated a shift of conserved cationic Arg3.29 from the UTP γ position to δ position of Up4U and Up4ribose. Sysnthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2′-Amino and 2-thio modifications synergized to enhance potency and selectivity; compound 8 (8 nM EC50) was 300-fold P2Y2-selective versus P2Y4. 2′-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance potency through a predicted hydrophilic interaction, possibly because of destabilization of the receptor-favored (N)-ribose conformation. This detailed view of P2Y2 receptor recognition suggests mutations for model validation.","journal":"UNC Libraries","year":2020,"id":142102,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":515149,"name":"Stefano Costanzi","orcid":"0000-0003-3183-7332","position":1,"is_corresponding":false},{"id":254876,"name":"Andrei A. Ivanov","orcid":"0000-0001-7476-1329","position":2,"is_corresponding":false},{"id":539023,"name":"Ingrid Fricks","orcid":null,"position":3,"is_corresponding":false},{"id":373375,"name":"Serge Van Calenbergh","orcid":"0000-0002-4201-1264","position":4,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":5,"is_corresponding":false},{"id":515775,"name":"T. Kendall Harden","orcid":null,"position":6,"is_corresponding":false},{"id":515776,"name":"Savitri Maddileti","orcid":null,"position":7,"is_corresponding":false},{"id":515146,"name":"Hyojin Ko","orcid":"0000-0002-1216-0066","position":8,"is_corresponding":false},{"id":540405,"name":"Liesbet Cosyn","orcid":null,"position":9,"is_corresponding":false},{"id":515147,"name":"Pedro Besada","orcid":"0000-0002-9985-9063","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:17:27.861239Z","pmid":null,"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":[]}