Integrative In Silico and In Vitro Screening of Low Molecular Weight Compounds Targeting SARS-CoV-2 RNA Elements

Area of Science:

• Drug discovery and development
• Structural biology
• Virology

Background:

• Viral RNA elements are crucial targets for antiviral therapies.
• Effective small molecule inhibitors are needed to combat RNA viruses like SARS-CoV-2.
• High-resolution structural data of viral RNA is essential for structure-based drug design.

Purpose of the Study:

• To develop and validate an integrated virtual and experimental screening strategy for identifying small molecules targeting SARS-CoV-2 RNA.
• To discover novel RNA-binding small molecules as starting points for antiviral drug development.
• To demonstrate the applicability of this strategy for other RNA-based pathogens.

Main Methods:

• Utilized Fragment Assembly of RNA with Full-Atom Refinement 2 (FARFAR2) ensembles of conserved SARS-CoV-2 RNA elements (SL1 and frameshift element) as structural targets.
• Performed virtual screening of three compound libraries against the selected RNA targets.
• Validated virtual screening hits using ligand- and target-based Nuclear Magnetic Resonance (NMR) experiments.

Main Results:

• Successfully identified small molecules with predicted binding affinity to SARS-CoV-2 RNA elements through virtual screening.
• Experimental NMR data confirmed the binding of selected small molecules to the target RNA structures.
• Demonstrated the efficiency and specificity of the integrated screening approach.

Conclusions:

• The combined virtual and NMR-based screening approach is an efficient method for discovering RNA-binding small molecules.
• This strategy accelerates the identification of lead compounds for RNA-targeted antiviral therapies.
• The approach is adaptable for discovering therapeutics against a broad range of RNA viruses, emphasizing the value of RNA structural data in drug discovery.