{"doi":"10.17615/d4ft-pp53","title":"Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning","abstract":"WD40 repeat-containing protein 91 (WDR91) regulates early-to-late endosome conversion and plays vital roles in endosome fusion, recycling, and transport. WDR91 was recently identified as a potential host factor for viral infection. We employed DNA-encoded chemical library (DEL) selection against the WDR domain of WDR91, followed by machine learning to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds identified a WDR91 selective compound <strong>1</strong>, with a <em>K</em><sub>D</sub> of 6 &plusmn; 2 &mu;M by surface plasmon resonance. The co-crystal structure confirmed the binding of <strong>1</strong> to the WDR91 side pocket, in proximity to cysteine 487, which led to the discovery of covalent analogues <strong>18</strong> and <strong>19</strong>. The covalent adduct formation for <strong>18</strong> and <strong>19</strong> was confirmed by intact mass liquid chromatography-mass spectrometry. The discovery of <strong>1</strong>, <strong>18</strong>, and <strong>19</strong>, accompanying structure-activity relationship, and the co-crystal structures provide valuable insights for designing potent and selective chemical tools against WDR91 to evaluate its therapeutic potential.","journal":"UNC Libraries","year":2025,"id":578263,"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":0.9542,"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":1025949,"name":"John W. 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