We are excited to share our latest work, now available on bioRxiv. SPIRAL (Structural Pockets and Interacting RNA-Associated Ligands) is a curated database of 1,098 RNA–small molecule co-crystal structures from the Protein Data Bank, built on a custom DSSR-based pipeline that extracts tertiary structural interaction fingerprints from every entry.
Using SPIRAL, we show that RNA functional class strongly governs how small molecules bind at the structural level — six mechanistically distinct binding modes emerge from unsupervised clustering, each reflecting a different chemical recognition strategy. To compare binding quality across these diverse modes, we introduce the Composite Binding Quality Score (CBQS), a seven-metric framework that ranks riboswitches as the highest-quality binders while identifying five quantifiable structural gaps in current regulatory RNA motif binders. Analysis of 275 affinity-characterized entries identifies C2′-endo sugar pucker count and total buried contact surface area as the dominant independent predictors of binding affinity — both enriched at the same tertiary structural sites most underengaged by existing compounds, pointing toward a concrete structural roadmap for improving both potency and selectivity simultaneously.
This work is a collaboration with Dr. Xiang-Jun Lu at Columbia University, developer of DSSR.