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

Abstract

Discoveries of RNA roles in cellular physiology and pathology are raising 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 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 to that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.

Pervasive Transcriptome Interactions of Protein-Targeted Drugs

“…Database curation of FDA-approved drugs. Lists of FDA-approved small-molecule drugs were acquired from a previous study 5 . Briefly, FDA-approved drugs were downloaded from DrugBank (v5.1.6, released on 04/22/2020.…”

“…Database curation of RNA-binding small-molecule ligands (RNA binders). The small-molecule (SM) RNA binders were downloaded from R-bind 2.0 5 on 05/24/2022. Molecules (131) with known PubChem Compound ID number (CID) were further used for Structural similarity analysis using the Tanimoto coefficient (Tc).…”

“…Indeed, our analysis suggests that nearly 35% of all small-molecule FDA-approved drugs chemically resemble at least one known RNA-binding molecule (Tanimoto coefficient 6 ≥0.7) (Fig. 1a-b and Supplementary file S1), and at least ten approved drugs are already documented as RNA binders in vitro (Supplementary file S2) 4,5 . Such chemical similarity with RNAbinding molecules also extends to drugs from preclinical studies and all phases in clinical trials (Fig.…”

“…These drug toxicities are commonly attributed to off-target binding to unintended cellular proteins 3 . Given RNA’s broad bioregulatory roles in human physiology and the structural resemblance of protein-targeted drugs with known RNA-binding molecules 4,5 ( Fig. 1a-c ), we hypothesize that many protein-targeted small-molecule drugs can interact with the human transcriptome (and RNA-protein interfaces) and may confer serious toxicity in patients.…”

“…1 | RBRP decodes transcriptome-interaction of protein-targeted small-molecule drugs in vivo. a, Structure key-based 2D Tanimoto coefficient (Tc) characterizes pairwise structural similarity between 131 reported small-molecule RNA binders 5 and 6043 drugs at various clinical phases. Number of small-molecule drugs at each clinical phase 24 (left panel).…”