{"doi":"10.1038/s41467-016-0009-6","title":"In situ click chemistry generation of cyclooxygenase-2 inhibitors","abstract":"<jats:title>Abstract</jats:title><jats:p>Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.</jats:p>","journal":"Nature Communications","year":2017,"id":12545,"datarank":1.3391767239317556,"base_score":8.927844826211702,"endowment":8.927844826211702,"self_citation_contribution":1.3391767239317556,"citation_network_contribution":0.0,"self_endowment_contribution":1.3391767239317556,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7538,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0497,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2017-02-23","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":98425,"name":"Jatinder Kaur","orcid":"0000-0001-6565-7909","position":1,"is_corresponding":false},{"id":98426,"name":"Melinda Wuest","orcid":"0000-0003-0735-2749","position":2,"is_corresponding":false},{"id":98427,"name":"Frank Wuest","orcid":"0000-0002-6705-6450","position":3,"is_corresponding":false},{"id":98424,"name":"Atul Bhardwaj","orcid":"0000-0001-6446-4267","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}