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

Abstract

Small molecules that target structured RNA hold therapeutic promise across a wide range of diseases, yet the structural principles governing RNA-ligand recognition remain poorly defined. We present SPIRAL (Structural Pockets and Interacting RNA-Associated Ligands), a curated database of 1,098 RNA-small molecule structures from the Protein Data Bank covering 1,137 ligand-binding events across six functional RNA categories. A customized pipeline built on DSSR (Dissecting the Spatial Structure of RNA) extracts structural interaction parameters from each complex, capturing stacking geometry, hydrogen-bond topology resolved by RNA moiety, groove engagement, and tertiary motif context. Unsupervised clustering of these fingerprints resolves six mechanistically distinct binding modes, the distribution of which is strongly governed by RNA functional class. To enable category-independent comparison of interaction quality across these diverse modes, we introduce the Composite Binding Quality Score (CBQS), a seven-metric framework that ranks riboswitches highest and regulatory RNA motifs lowest among the six categories. Across 275 affinity-characterized entries, C2'-endo sugar pucker count and total buried contact surface area emerge as the dominant predictors of binding affinity, converging with the structural features most underengaged by current regulatory RNA motif binders. SPIRAL provides a data-driven foundation for the rational design of next-generation RNA-targeted therapeutics.