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 NA-targeted oactive ligad atabase (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.

Frameworks for targeting RNA with small molecules.

Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins, RNA molecules play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. Through these interactions, RNAs mediate cellular processes such as the regulation of gene transcription and the enhancement or inhibition of protein activity.

Template-guided selection of RNA ligands using imine-based dynamic combinatorial chemistry.

This study establishes the applicability of imine-based dynamic combinatorial chemistry to discover non-covalent ligands for RNA targets. We elucidate properties underlying the reactivity of arylamines and demonstrate target-guided amplification of tight binders in an amiloride-based dynamic library.

Driving factors in amiloride recognition of HIV RNA targets.

Noncoding RNAs are increasingly promising drug targets yet ligand design is hindered by a paucity of methods that reveal driving factors in selective small molecule : RNA interactions, particularly given the difficulties of high-resolution structural characterization. HIV RNAs are excellent model systems for method development given their targeting history, known structure-function relationships, and the unmet need for more effective treatments. Herein we report a strategy combining synthetic diversification, profiling against multiple RNA targets, and predictive cheminformatic analysis to identify driving factors for selectivity and affinity of small molecules for distinct HIV RNA targets.

Understanding the Contributions of Conformational Changes, Thermodynamics, and Kinetics of RNA-Small Molecule Interactions.

The implication of RNA in multiple cellular processes beyond protein coding has revitalized interest in the development of small molecules for therapeutically targeting RNA and for further probing its cellular biology. However, the process of rationally designing such small molecule probes is hampered by the paucity of information about fundamental molecular recognition principles of RNA. In this Review, we summarize two important and often underappreciated aspects of RNA-small molecule recognition: RNA conformational dynamics and the biophysical properties of interactions of small molecules with RNA, specifically thermodynamics and kinetics.