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 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 () 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.

Protein-Based Virtual Screening Tools Applied for RNA–Ligand Docking Identify New Binders of the preQ1-Riboswitch

“…Targeting RNA with small molecules, however, is still a novel concept, and only one molecule except ribosome-targeting antibiotics is approved by the FDA. With Risdiplam, , the first approved small-molecule splicing modifier is available for the treatment of spinal muscular atrophy, and further splicing modifiers, micro-RNA (miRNA) ligands, and binders of extended trinucleotide repeats are under elucidation for many indications including cancer ,− and neurological and genetic disorders. ,− While only around 1.5% of the human genome is transcribed into proteins, the common drug-targets, about 70–90% is transcribed into RNA. ,, These mainly noncoding RNAs (ncRNAs) represent promising targets for novel therapeutics. Furthermore, viral RNAs like the SARS-CoV-2 frameshift pseudoknot, , enterovirus internal ribosomal entry site, or the HIV trans -activation response element (TAR) , were successfully targeted with small molecules.…”

Recognizing the power of machine learning and other computational methods to accelerate progress in small molecule targeting of RNA

“…17 Comparison of the properties found in FDA-approved SM drugs, as a source of bioactive protein ligands, revealed that R-BIND occupied a specific subregion of the space occupied by the FDA library, considered as "drug-like" space (Figure 2A). 23 Here, k-NN clustering analysis determined the quantitative overlap of the two libraries, revealing that the 31% of R-BIND SM and 9% of FDA library overlap with the other library's cluster. 17 The differentiation between R-BIND and FDA libraries was described in terms of physicochemical, structural and spatial descriptors.…”

“…17 The differentiation between R-BIND and FDA libraries was described in terms of physicochemical, structural and spatial descriptors. 23 Several physicochemical and structural descriptors were significantly different between the two libraries. Cell-based partitioning assisted the quantitative comparison of SM distribution in the PMI triangle (Figure 2B), and cumulative frequency distribution found that while both are enriched with rod-like SM, R-BIND is significantly more enriched than the FDA library.…”

“…17 Created in 2017, R-BIND incorporated molecules reported in the literature for in vitro binding to non-ribosomal RNA through non-covalent interactions and was the first database to include biological activity in cellular and/or animal models as an essential criterion. 17,22,23 Aminoglycosides (Ags), covalent ligands, peptides, and oligonucleotides were excluded in this analysis due to dramatic differences in molecular properties relative to traditional "drug-like" small molecules. R-BIND characterized ligands with 20 physicochemical and structural descriptors as well as three-dimensional shapes, i.e., disk-, rod-, and sphere-like, using principal moments of inertia (PMI).…”

Targeting Pathogenic DNA and RNA Repeats: A Conceptual Therapeutic Way for Repeat Expansion Diseases

“…Disney's group has developed the Inforna platforms that integrate RNA secondary structure prediction and data libraries of RNA‐ligand interactions from an in‐house two‐dimensional combinatorial screening, [63] and the Inforna 2.0 successfully screened the bis‐benzimidazole that targeted rCUG repeats to rescue cellular toxicity (Table 1). [53,63a] As a complement to the Inforna platforms, the R‐BIND databases developed by Hargrove's group use the data of RNA‐ligand interactions from literature‐reported bioactive small molecules, [64] and the R‐BIND 2.0 could identify DB213 as the ligand for rCAG repeats as mentioned above [50,64a] . The recently reported G4LDB2.2 database can search and design both DNA and RNA G‐quadruplex ligands [65] .…”