Identifying small-molecules binding sites in RNA conformational ensembles with SHAMAN.

The rational targeting of RNA with small molecules is hampered by our still limited understanding of RNA structural and dynamic properties. Most in silico tools for binding site identification rely on static structures and therefore cannot face the challenges posed by the dynamic nature of RNA molecules. Here, we present SHAMAN, a computational technique to identify potential small-molecule binding sites in RNA structural ensembles. SHAMAN enables exploring the conformational landscape of RNA with atomistic molecular dynamics simulations and at the same time identifying RNA pockets in an efficient way with the aid of probes and enhanced-sampling techniques. In our benchmark composed of large, structured riboswitches as well as small, flexible viral RNAs, SHAMAN successfully identifies all the experimentally resolved pockets and ranks them among the most favorite probe hotspots. Overall, SHAMAN sets a solid foundation for future drug design efforts targeting RNA with small molecules, effectively addressing the long-standing challenges in the field.

HARIBOSS: a curated database of RNA-small molecules structures to aid rational drug design.

MOTIVATION: RNA molecules are implicated in numerous fundamental biological processes and many human pathologies, such as cancer, neurodegenerative disorders, muscular diseases and bacterial infections. Modulating the mode of action of disease-implicated RNA molecules can lead to the discovery of new therapeutical agents and even address pathologies linked to 'undruggable' protein targets. This modulation can be achieved by direct targeting of RNA with small molecules. As of today, only a few RNA-targeting small molecules are used clinically. One of the main obstacles that have hampered the development of a rational drug design protocol to target RNA with small molecules is the lack of a comprehensive understanding of the molecular mechanisms at the basis of RNA-small molecule (RNA-SM) recognition. RESULTS: Here, we present Harnessing RIBOnucleic acid-Small molecule Structures (HARIBOSS), a curated collection of RNA-SM structures determined by X-ray crystallography, nuclear magnetic resonance spectroscopy and cryo-electron microscopy. HARIBOSS facilitates the exploration of drug-like compounds known to bind RNA, the analysis of ligands and pockets properties and ultimately the development of in silico strategies to identify RNA-targeting small molecules. AVAILABILITY AND IMPLEMENTATION: HARIBOSS can be explored via a web interface available at http://hariboss.pasteur.cloud. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.