{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T19:07:22Z","timestamp":1778699242575,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,13]]},"group-title":"Bioinformatics","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NS116846"],"award-info":[{"award-number":["NS116846"]}]},{"name":"Muscular Dystrophy Association","award":["963835"],"award-info":[{"award-number":["963835"]}]},{"name":"German Research Foundation","award":["515396515"],"award-info":[{"award-number":["515396515"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,11]]},"abstract":"<jats:p>Structured RNAs cause human diseases but remain challenging to target selectively with small molecules. Here, we report a chemoinformatics-guided discovery framework that integrates fingerprint-based molecular design, experimental validation, and mechanistic profiling to identify small molecules that bind highly structured, disease-associated RNAs. Using an RNA-binder fingerprint derived from known ligands, a Tversky similarity screen of &gt;8 million compounds yielded a 150-member library enriched in chemical space for RNA-active scaffolds. Target engagement and cell-based assays identified multiple selective ligands for the pathogenic expanded triplet repeat, r(CUG)exp, that causes myotonic dystrophy type 1 (DM1) by binding and sequestering the RNA-binding protein muscleblind-like 1 (MBNL1). Biophysical and single-molecule analyses revealed that the small molecules bind the 1x1 nucleotide U\/U internal loops formed when r(CUG)exp folds, partially block MBNL1 binding, and modulate RNA folding equilibria. Two optimized scaffolds rescued MBNL1-dependent splicing in patient-derived myotubes with micromolar potency and minimal cytotoxicity. This study establishes a generalizable, data-driven platform for discovering drug-like RNA-binding lead small molecules and demonstrates its application to the toxic repeat expansion RNA underlying DM1.<\/jats:p>","DOI":"10.64898\/2026.05.08.723748","type":"posted-content","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:10:21Z","timestamp":1778695821000},"source":"Crossref","is-referenced-by-count":0,"title":["A chemoinformatics-guided platform for efficient discovery of RNA-binding small molecules: Proof-of-concept for myotonic dystrophy type 1"],"prefix":"10.64898","author":[{"given":"amirhossein","family":"taghavi","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Herbert Wertheim UF Scripps Institute  for Biomedical Innovation & Technology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingsong","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiyuan","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick R. 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