R‑BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

Discoveries
of RNA roles in cellular physiology and pathology are
increasing the need for new tools that modulate the structure and
function of these biomolecules, and small molecules are proving useful.
In 2017, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND) and discovered distinguishing physicochemical properties
of RNA-targeting ligands, leading us to propose the existence of an
“RNA-privileged” chemical space. Biennial updates of
the database and the establishment of a website platform (rbind.chem.duke.edu) have
provided new insights and tools to design small molecules based on
the analyzed physicochemical and spatial properties. In this report
and R-BIND 2.0 update, we refined the curation approach and ligand
classification system as well as conducted analyses of RNA structure
elements for the first time to identify new targeting strategies.
Specifically, we curated and analyzed RNA target structural motifs
to determine the properties of small molecules that may confer selectivity
for distinct RNA secondary and tertiary structures. Additionally,
we collected sequences of target structures and incorporated an RNA
structure search algorithm into the website that outputs small molecules
targeting similar motifs without a priori secondary structure knowledge.
Cheminformatic analyses revealed that, despite the 50% increase in
small
molecule library size, the distinguishing properties of R-BIND ligands
remained significantly different from that of proteins and are therefore
still relevant to RNA-targeted probe discovery. Combined, we expect
these novel insights and website features to enable the rational design
of RNA-targeted ligands and to serve as a resource and inspiration
for a variety of scientists interested in RNA targeting.