A chemoinformatics-guided platform for efficient discovery of RNA-binding small molecules: Proof-of-concept for myotonic dystrophy type 1

taghavi, a.; Shan, J.; Yao, X.; Zanon, P. R. A.; Sung, K.; Simba-Lahuas, A.; Gorlach, S.; Labuhn, H.; Salthouse, D.; Wang, Z.; Feri, A.; Disney, M. D.

doi:10.64898/2026.05.08.723748

bioRxiv · 10.64898/2026.05.08.723748

A chemoinformatics-guided platform for efficient discovery of RNA-binding small molecules: Proof-of-concept for myotonic dystrophy type 1

taghavi, a.·Shan, J.·Yao, X.·Zanon, P. R. A.·Sung, K.·Simba-Lahuas, A.·Gorlach, S.·Labuhn, H.·Salthouse, D.·Wang, Z.·Feri, A.·Disney, M. D.

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Abstract

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 >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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/723748v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a87b41org.highwire.dtl.DTLVardef@340a14org.highwire.dtl.DTLVardef@81b583org.highwire.dtl.DTLVardef@1b3ba14_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

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taghavi, a., Shan, J., Yao, X., Zanon, P. R. A., Sung, K., Simba-Lahuas, A., Gorlach, S., Labuhn, H., Salthouse, D., Wang, Z., Feri, A., Disney, M. D.. 2026-05-13. A chemoinformatics-guided platform for efficient discovery of RNA-binding small molecules: Proof-of-concept for myotonic dystrophy type 1. https://doi.org/10.64898/2026.05.08.723748

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