Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like...

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• The therapeutic potential of targeting RNA with small molecules is recognized, but the necessary physicochemical properties for selective binding are not well understood.
• Identifying small molecules that bind RNA is crucial for developing novel therapeutics.

Purpose of the Study:

• To investigate the druggability of RNA targets using small molecules.
• To identify specific chemical properties that promote selective binding of small molecules to RNA.
• To develop a methodology applicable to RNA-focused drug discovery.

Main Methods:

• Employed affinity mass spectrometry with the Automated Ligand Identification System (ALIS).
• Screened 42 diverse RNA targets against approximately 50,000 drug-like small molecules and 5,100 tool compounds.
• Utilized naïve Bayesian models to compare RNA-small molecule interactions with protein-small molecule interactions and identify RNA-selective chemical features.

Main Results:

• Generated a comprehensive dataset of RNA-small molecule interactions.
• Identified specific physicochemical properties that bias small molecules toward binding RNA.
• Developed an RNA-focused compound library (~3800 molecules) with enhanced propensity for RNA binding.

Conclusions:

• Significantly advanced the understanding of chemical properties governing small molecule-RNA binding.
• The developed methodology and identified features are broadly applicable to RNA-targeted drug discovery.
• This work provides a foundation for designing novel RNA-binding small molecule therapeutics.