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Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
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RNA-Focused DNA-Encoded Library Construction, Screening, and Integration of Docking Identify Bioactive Ligands of
Xueyi Yang1,2, Amirhossein Taghavi1, Yoshihiro Akahori1
1Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458, United States.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Researchers developed a DNA-encoded library (DEL) to discover small molecules targeting toxic RNA repeats. This approach successfully identified and optimized drug leads for diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Area of Science:
- Medicinal Chemistry
- RNA Therapeutics
- Drug Discovery
Background:
- Disease-associated RNAs are emerging as key therapeutic targets for small-molecule drugs.
- DNA-encoded libraries (DELs) show promise for identifying RNA-binding small molecules, complementing their established use in protein ligand discovery.
Purpose of the Study:
- To construct a diverse, solid-phase DEL enriched in RNA-binding scaffolds.
- To identify small-molecule ligands for the toxic r(G4C2) RNA repeat expansion associated with ALS and FTD.
- To demonstrate the integration of DEL technology with computational methods for rational RNA-targeted drug design.
Main Methods:
- A specialized DEL was synthesized and screened against the r(G4C2) RNA.
- Large-scale molecular docking, physicochemical analysis, and structure-activity relationship (SAR) studies were employed to analyze DEL selection outcomes.
- Lead compound optimization was guided by docking poses and NMR structures.
Main Results:
- Significant correlations were found between molecular docking predictions and experimental enrichment data.
- The identified lead compound was optimized into analogs with improved binding affinity and bioactivity.
- The study validated a combined DEL and computational approach for RNA ligand discovery.
Conclusions:
- The developed platform effectively identifies RNA-targeting small molecules.
- This integrated approach accelerates the rational design and optimization of RNA-targeted therapeutics.
- The findings highlight a versatile strategy for discovering novel treatments for RNA-mediated diseases.
