Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA‐Targeted Bioactive Ligands

Abstract

While amyriad non-coding RNAs are knowntobe essential in cellular processes and misregulated in diseases,the development of RNA-targeted small molecule probes has met with limited success.T oe lucidate the guiding principles for selective small molecule/RNArecognition, we analyzed cheminformatic and shape-based descriptors for 104 RNA-targeted ligands with demonstrated biological activity (RNA-targeted BIoactive ligaNd Database,R -BIND). We then compared R-BIND to both FDA-approved small molecule drugs and RNA ligands without reported bioactivity.S everal striking trends emerged for bioactive RNAligands,including:1)Compliance to medicinal chemistry rules,2 )distinctive structural features, and 3) enrichment in rod-like shapes over others.T his work provides unique insights that directly facilitate the selection and synthesis of RNA-targeted libraries with the goal of efficiently identifying selective small molecule ligands for therapeutically relevant RNAs.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space

“…For comparison, we included approved drugs, ALIS protein binders, and literature small molecule and multivalent RNA binders from the RNA-Targeted Bioactive Ligand Database (R-BIND). 22 Consistent with the findings of Morgan et al, 22 we observe that the majority of RNA binders and protein binders overlap within drug-like chemical space, although there are a few RNA-binding and protein-binding compounds that occupy space that is distinct from the drug-like compounds (Fig. 4).…”

Mechanistic studies of a small-molecule modulator of SMN2 splicing

“…Recently, small-molecule RNA-targeted therapeutics have drawn considerable attention from both the pharmaceutical industry and academic laboratories (11,(46)(47)(48). One such molecule, RG-7916, was originally identified through a phenotypic high-throughput screen.…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…In addition, RNAs are generally more hydrophilic than a typical protein (McCown et al, 2017;Mustoe et al, 2018). Surrounded by an ion atmosphere under physiologic conditions, the folding and structure of electrostatic RNA, especially the sites for ligand binding, are relatively less understood, and they are very different from those found in proteins (Hermann, 2016;Morgan et al, 2017Morgan et al, , 2018.…”