{"doi":"10.17615/ace2-qp40","title":"Validating the fragment-based drug discovery strategy for targeting biological RNAs: Lead fragments specifically bind and remodel the TPP riboswitch","abstract":"Thiamine pyrophosphate (TPP) riboswitches regulate essential genes in bacteria by changing conformation upon binding intracellular TPP. Previous studies using fragment-based approaches identified small molecule “fragments” that bind this gene-regulatory mRNA domain. Crystallographic studies now show that, despite having micromolar Kds, four different fragments bind the TPP riboswitch site-specifically, occupying the pocket that recognizes the aminopyrimidine of TPP. Unexpectedly, the unoccupied site that would recognize the pyrophosphate of TPP rearranges into a structure distinct from that of the cognate complex. This idiosyncratic fragment-induced conformation, also characterized by small-angle X-ray scattering (SAXS) and chemical probing (SHAPE), represents a possible mechanism for adventitious ligand discrimination by the riboswitch, and suggests that off-pathway conformations of RNAs can be targeted for drug development. Our structures, together with previous screening studies, demonstrate the feasibility of fragment-based drug discovery against RNA targets.","journal":"UNC Libraries","year":2020,"id":138005,"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":0.9505,"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":331047,"name":"Chris Abell","orcid":"0000-0001-9174-1987","position":1,"is_corresponding":false},{"id":5954,"name":"Kevin M. Weeks","orcid":"0000-0002-6748-9985","position":2,"is_corresponding":false},{"id":598726,"name":"Philip Homan","orcid":"0000-0002-3389-4931","position":3,"is_corresponding":false},{"id":256530,"name":"Alison G. Smith","orcid":"0000-0001-6511-5704","position":4,"is_corresponding":false},{"id":599408,"name":"K.D. Warner","orcid":null,"position":5,"is_corresponding":false},{"id":321054,"name":"A.R. Ferré-D′Amaré","orcid":"0000-0003-4549-1619","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:59.449905Z","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":[]}