{"doi":"10.1101/2025.07.23.666362","title":"Inhibitor fluorination pattern tunes chemically induced protein dimerization","abstract":"Abstract Chemically induced dimerization of proteins is a powerful approach to regulate biomolecular functions through small molecule ligands acting as “molecular glues”. Here, we demonstrate that simple, thienopyrimidinone scaffold-based inhibitors efficiently promote homodimerization of an essential oxidoreductase from the human pathogenic parasite Trypanosoma brucei through selective covalent attachment and self-assembly. A fluorine walk strategy, commonly used to optimize small molecule properties, resulted in tuning induced dimer affinity across two orders of magnitude. NMR spectroscopy, MD simulations, chromatography, multi-angle light scattering, mass spectrometry, calorimetry, and functional assays reveal how the inhibitor fluorination pattern alters the dynamics and interactions of the enzyme-bound inhibitor and surface-exposed aromatic protein side chains, affecting both enzyme inhibition kinetics and induced dimerization. This work highlights how site-specific fluorination can modulate protein interactions and offers a framework for the design of novel molecular glues with broad applications in chemical biology and drug development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558718,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1459524,"name":"Jean-Martin Harder","orcid":"0000-0002-2322-5371","position":1,"is_corresponding":false},{"id":1459933,"name":"Marco D. Preuss","orcid":null,"position":2,"is_corresponding":false},{"id":1244938,"name":"Charlotte Guhl","orcid":"0000-0002-5301-0064","position":3,"is_corresponding":false},{"id":1459525,"name":"Shuai‐Bing Zhang","orcid":"0000-0003-4455-0971","position":4,"is_corresponding":false},{"id":1459526,"name":"Annika Wagner","orcid":"0000-0001-9953-5299","position":5,"is_corresponding":false},{"id":1459934,"name":"Nicole Bader","orcid":null,"position":6,"is_corresponding":false},{"id":1118905,"name":"Pierre Stallforth","orcid":"0000-0001-7260-9921","position":7,"is_corresponding":false},{"id":585998,"name":"Markus Lakemeyer","orcid":"0000-0001-6580-3275","position":8,"is_corresponding":false},{"id":36216,"name":"Hermann Schindelin","orcid":"0000-0002-2067-3187","position":9,"is_corresponding":false},{"id":1459527,"name":"Till Opatz","orcid":"0000-0002-3266-4050","position":10,"is_corresponding":false},{"id":472782,"name":"Ute A. Hellmich","orcid":"0000-0001-7162-285X","position":11,"is_corresponding":false},{"id":1459523,"name":"Eric Schwegler","orcid":"0000-0003-3635-7418","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40766609","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":[]}