NMR and SPR Fragment-Based Screening Can Produce Novel High Affinity Small Molecule Hits against Structured RNAs

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Structural Biology

Background:

• Noncoding RNAs (ncRNAs) constitute a significant portion of the human transcriptome, playing crucial roles in cellular functions.
• Targeting ncRNAs with small molecules is a promising therapeutic strategy, but knowledge of RNA-ligand structures and interactions is limited.
• Understanding structure-interaction relationships is key to developing effective RNA-targeting therapeutics.

Purpose of the Study:

• To develop and validate a fragment-based screening approach for identifying small molecules that bind to RNA.
• To investigate RNA-ligand interactions using a model RNA aptamer system.
• To provide insights into the structure-interaction relationships of RNA-targeting small molecules.

Main Methods:

• Fragment-based screening using biophysical assays to identify binding fragments.
• Utilized a theophylline-binding RNA aptamer as a model system.
• Combined biophysical data with computational docking to generate RNA-ligand complex models.

Main Results:

• Identified high-affinity fragment hits that bind to the model RNA aptamer.
• Generated models of RNA-ligand complexes, revealing key interaction insights.
• Demonstrated the feasibility of the fragment-based approach for discovering RNA-targeting molecules.

Conclusions:

• The fragment-based screening approach is effective for identifying high-affinity RNA-targeting small molecules.
• This method provides valuable insights into RNA-fragment interactions with limited structural information.
• The findings support the potential of this approach for developing novel RNA-based therapeutics.