{"doi":"10.1101/2024.06.21.600119","title":"NMR structures of small molecules bound to a model of an RNA CUG repeat expansion","abstract":"ABSTRACT Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington’s disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington’s disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG) exp . The RNA folds into a hairpin structure with a periodic array of 1×1 nucleotide UU loops (5’C U G/3’G U C; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function. Here, we report NMR-refined structures of single 5’C U G/3’G U C motifs in complex with three different small molecules, a diguandinobenzoate ( 1 ), a derivative of 1 where the guanidino groups have been exchanged for imidazole ( 2 ), and a quinoline with improved drug-like properties ( 3 ). These structures were determined using nuclear magnetic resonance (NMR) spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1 , 2 , and 3 formed stacking and hydrogen bonding interactions with the 5’C U G/3’G U C motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG) exp . As the first ever reported structures of RNA r(CUG) repeats bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488644,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":712050,"name":"Amirhossein Taghavi","orcid":"0000-0001-9270-9145","position":1,"is_corresponding":false},{"id":297138,"name":"Alexander J. Frank","orcid":null,"position":2,"is_corresponding":false},{"id":297144,"name":"Matthew A. Fountain","orcid":null,"position":3,"is_corresponding":false},{"id":333359,"name":"Shruti Choudhary","orcid":"0000-0002-6146-7224","position":4,"is_corresponding":false},{"id":452188,"name":"Soma Roy","orcid":null,"position":5,"is_corresponding":false},{"id":249554,"name":"Jessica L. Childs‐Disney","orcid":"0009-0001-7829-3240","position":6,"is_corresponding":false},{"id":249561,"name":"Matthew D. Disney","orcid":"0000-0001-8486-1796","position":7,"is_corresponding":false},{"id":296421,"name":"Jonathan L. Chen","orcid":"0000-0001-7907-9732","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:19.655720Z","pmid":"38948793","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":[]}