Structural Pockets and Interacting RNA-Associated Ligands (SPIRAL): A DSSR-enabled Meta-Analysis of RNA-Small...

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Small molecules targeting structured RNA offer therapeutic potential for various diseases.
• Understanding RNA-ligand interactions is crucial for developing effective therapeutics.
• Current knowledge of structural principles governing RNA-ligand recognition is limited.

Purpose of the Study:

• To create a comprehensive database (SPIRAL) of RNA-small molecule structures.
• To elucidate the structural principles and binding modes of RNA-ligand recognition.
• To identify key structural features that predict binding affinity and guide drug design.

Main Methods:

• Curated 1,098 RNA-small molecule structures from the Protein Data Bank.
• Utilized a pipeline based on DSSR to extract structural interaction parameters.
• Applied unsupervised clustering to identify distinct binding modes.
• Developed the Composite Binding Quality Score (CBQS) for comparing interaction quality.

Main Results:

• Identified six mechanistically distinct RNA-ligand binding modes.
• Demonstrated that RNA functional class dictates binding strategies.
• Established CBQS ranking: riboswitches highest, regulatory RNA motifs lowest.
• Found C2'-endo sugar pucker and buried contact surface area predict binding affinity.

Conclusions:

• RNA-ligand recognition involves diverse chemical strategies dependent on RNA function.
• SPIRAL and CBQS provide frameworks for analyzing and comparing RNA-ligand interactions.
• Targeting junction loops and pseudoknots can enhance drug potency and selectivity.