{"doi":"10.1039/d3sc03613h","title":"Data-driven discovery of innate immunomodulators <i>via</i> machine learning-guided high throughput screening","abstract":"HTS, we performed an active learning-guided traversal of a 139 998 molecule library. After sampling only ∼2% of the library, we discovered viable molecules with unprecedented immunomodulatory capacity, including those capable of suppressing NF-κB activity by up to 15-fold, elevating NF-κB activity by up to 5-fold, and elevating IRF activity by up to 6-fold. We extracted chemical design rules identifying particular chemical fragments as principal drivers of specific immunomodulation behaviors. We validated the immunomodulatory effect of a subset of our top candidates by measuring cytokine release profiles. Of these, one molecule induced a 3-fold enhancement in IFN-β production when delivered with a cyclic di-nucleotide stimulator of interferon genes (STING) agonist. In sum, our machine learning-enabled screening approach presents an efficient immunomodulator discovery pipeline that has furnished a library of novel small molecules with a strong capacity to enhance or suppress innate immune signaling pathways to shape and improve prophylactic vaccination and immunotherapies.","journal":"Chemical Science","year":2023,"id":343450,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9306,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":730999,"name":"Jeremiah Kim","orcid":"0000-0003-0094-9171","position":1,"is_corresponding":false},{"id":1081453,"name":"Carman KM IP","orcid":null,"position":2,"is_corresponding":false},{"id":1081454,"name":"Azadeh Bahmani","orcid":null,"position":3,"is_corresponding":false},{"id":317051,"name":"Qing Chen","orcid":"0000-0002-7360-5700","position":4,"is_corresponding":false},{"id":464964,"name":"Matthew G. Rosenberger","orcid":"0000-0002-0595-5338","position":5,"is_corresponding":false},{"id":464966,"name":"Aaron P. Esser‐Kahn","orcid":"0000-0003-1273-0951","position":6,"is_corresponding":false},{"id":106916,"name":"Andrew L. Ferguson","orcid":"0000-0002-8829-9726","position":7,"is_corresponding":false},{"id":1081000,"name":"Yifeng Tang","orcid":"0000-0003-4247-6712","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:11:21.758449Z","pmid":"38020385","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":[]}