R-BIND: An Interactive Database for Exploring and Developing RNA-Targeted Chemical Probes

Abstract

While the opportunities available for targeting RNA with small molecules have been widely appreciated, the challenges associated with achieving specific RNA recognition in biological systems have hindered progress and prevented many researchers from entering the field. To facilitate the discovery of RNA-targeted chemical probes and their subsequent applications, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND). This collection contains an array of information on reported chemical probes that target non-rRNA and have biological activity, and analysis has led to the discovery of RNA-privileged properties. Herein, we developed an online platform to make this information freely available to the community, offering search options, a suite of tools for probe development, and an updated R-BIND data set with detailed experimental information for each probe. We repeated the previous cheminformatics analysis on the updated R-BIND list and found that the distinguishing physicochemical, structural, and spatial properties remained unchanged, despite an almost 50% increase in the database size. Further, we developed several user-friendly tools, including queries based on cheminformatic parameters, experimental details, functional groups, and substructures. In addition, a nearest neighbor algorithm can assess the similarity of user-uploaded molecules to R-BIND ligands. These tools and resources can be used to design small molecule libraries, optimize lead ligands, or select targets, probes, assays, and control experiments. Chemical probes are critical to the study and discovery of novel functions for RNA, and we expect this resource to greatly assist researchers in exploring and developing successful RNA-targeted probes.

Unnatural bases for recognition of noncoding nucleic acid interfaces

“…In this review, we primarily discuss unnatural bases designed to target hydrogen-bonding information at noncanonical sites in structured DNA and RNA, while drawing lessons from coding and library approaches that shape-selectively target binding pockets in nucleic acid folds. [2][3][4][5][6][7] Thoroughly reviewed work from the Dervan lab [8] on minor groove targeting polypyrrole amides [9,10] will not be discussed in depth here, though these systems have been studied in a wide range of applications, including DNase and restriction enzyme inhibition, [11,12] site-specific cleavage, [13] replication/ transcription termination, [14] and dicer inhibition. [15] Similarly, due to space limitations, we will not deeply discuss small molecule reagents, [16][17][18] library approaches to binding nucleic acid, [2,4,7] and more recently reviewed triplex motifs.…”

DrugPred_RNA – Structure-Based Druggability Predictions for RNA Binding Sites

“…The R-BIND database links binding data also to RNA crystal structures, but for only five of the ligands in this database a complex structure is available in the Protein Data Bank (PDB). 28 Due to the paucity of suitable data, we opted to train and validate our modified DrugPred model, which we termed DrugPred_RNA, on protein data. Subsequently, DrugPred_RNA was used for druggability predictions of RNA structures including the ribosome.…”

Target-Directed Approaches for Screening Small Molecules against RNA Targets

“…This knowledge can be used to identify scaffolds of interest for RNA-binding optimization or tools for screening approaches. Several freely available databases (Inforna, 19 SMMRNA, 183 R-BIND, 184 G4LDB, 185 and NALDB 186 ) documenting a catalog of small molecule-RNA interactions exist, with insight ranging from basic selectivity and affinity measurements to detailed compound parameters and experimental insight. Inforna (https://disney.florida.scripps.edu/software/) is a database of experimentally determined, privileged RNA motif-small molecule interactions alongside interactions reported in the literature.…”