Ligand-binding pockets in RNA and where to find them DOI Creative Commons
Seth D. Veenbaas, Jordan T. Koehn, Patrick S. Irving

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(17)

Published: April 22, 2025

RNAs are critical regulators of gene expression, and their functions often mediated by complex secondary tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire an RNA. The broad potential to biological function intentionally via RNA–ligand interactions remains unrealized, however, due challenges identifying compact motifs ability bind ligands good physicochemical properties (often termed drug-like). Here, we devise fpocketR , a computational strategy that accurately detects pockets capable binding drug-like Remarkably few, roughly 50, such have ever been visualized. We experimentally confirmed ligandability novel detected using fragment-based approach introduced here, Frag-MaP, sites cells. Analysis validated Frag-MaP reveals dozens able ligands, supports model for structural quality creates framework understanding ligand-ome.

Language: Английский

fpocketR: A platform for identification and analysis of ligand-binding pockets in RNA DOI Creative Commons
Seth D. Veenbaas, Simon Felder, Kevin M. Weeks

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 29, 2025

Abstract Small molecules that bind specific sites in RNAs hold promise for altering RNA function, manipulating gene expression, and expanding the scope of druggable targets beyond proteins. Identifying binding can engage ligands with good physicochemical properties remains a significant challenge. fpocketR is software package identifying, characterizing, visualizing ligand-binding RNA. was optimized, through comprehensive analysis currently available RNA-ligand complexes, to identify pockets able small possessing favorable properties, generally termed drug-like. Here, we demonstrate use analyze interactions novel large RNAs, assess ensembles structure models, dynamic systems. performs best structures visualized at high (≤3.5 Å) resolution, but also provides useful information lower resolution computational models. powerful, freely tool discovery molecules.

Language: Английский

Citations

0
Ligand-binding pockets in RNA and where to find them DOI Creative Commons
Seth D. Veenbaas, Jordan T. Koehn, Patrick S. Irving

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(17)

Published: April 22, 2025

RNAs are critical regulators of gene expression, and their functions often mediated by complex secondary tertiary structures. Structured regions in RNA can selectively interact with small molecules—via well-defined ligand-binding pockets—to modulate the regulatory repertoire an RNA. The broad potential to biological function intentionally via RNA–ligand interactions remains unrealized, however, due challenges identifying compact motifs ability bind ligands good physicochemical properties (often termed drug-like). Here, we devise fpocketR , a computational strategy that accurately detects pockets capable binding drug-like Remarkably few, roughly 50, such have ever been visualized. We experimentally confirmed ligandability novel detected using fragment-based approach introduced here, Frag-MaP, sites cells. Analysis validated Frag-MaP reveals dozens able ligands, supports model for structural quality creates framework understanding ligand-ome.

Language: Английский

Citations

0