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

Morgan, Brittany S.; Forte, Jordan E; Culver, Rebecca; Zhang, Yuqi; Hargrove, Amanda E.

doi:10.1002/anie.201707641

Cited by 100 publications

(111 citation statements)

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“…Recently, we compiled the R NA - targeted BI oactive liga N d D atabase (R-BIND), which comprised organic small molecules that target non-ribosomal RNAs and show activity in cell culture or animal models ( 22 ). For this Survey, the compilation was updated to include chemical probe discoveries through May 2017 for a total of 116 chemical probes (see Supplementary Material , R-BIND_1-1.xls).…”

Section: Introductionmentioning

confidence: 99%

Insights into the development of chemical probes for RNA

Morgan

Forte

Hargrove

2018

Nucleic Acids Research

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Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND). In this survey, we examine the RNA targets, design and discovery strategies, and chemical probe characterization techniques of these ligands. We discuss the applicability of current tools to identify and evaluate RNA-targeted chemical probes, suggest criteria to assess the quality of RNA chemical probes and targets, and propose areas where new tools are particularly needed. We anticipate that this knowledge will expedite the discovery of RNA-targeted ligands and the next phase of the RNA revolution.

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Section: Introductionmentioning

confidence: 99%

Insights into the development of chemical probes for RNA

Morgan

Forte

Hargrove

2018

Nucleic Acids Research

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“…Further, the energetic cost of breaking intramolecular interactions may be in part responsible for the decreased binding strengths in these two sublibraries. Ultimately, we propose that these sublibraries are less likely to achieve extended, rod‐like shapes that are important for selective RNA recognition …”

Section: Figurementioning

confidence: 99%

“…PMI calculations revealed striking sublibrary‐based differences in small molecule shapes, a diversity deemed important for screening libraries but often difficult to achieve with scaffold‐based libraries of similar size . Consistent with our previous observations, the most promising ligands had rod‐like shapes in this analysis. The more disc and sphere‐like DPF ligands were predicted to have increased intramolecular interactions and scaffold dihedral angles, which generally correlated with a decrease in binding strengths for the triple helix.…”

Section: Figurementioning

confidence: 99%

“…Furthermore, as the intramolecular interactions identified in this study formed through chemotypes that are commonly found in RNA‐binding small molecules, such as aromatic and heteroatom‐containing moieties, we suggest that future efforts to design RNA‐targeted libraries should investigate the possibility of intramolecular interactions within ligands containing these chemotypes . Lastly, we note that these interactions should be taken into consideration when performing docking studies to rank RNA:ligand affinities, as the analysis of energetically inaccessible conformations due to intramolecular interactions has led to dead‐end designs in protein‐based experiments .…”

Section: Figurementioning

confidence: 99%

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Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

Donlic

Morgan

et al. 2018

Angewandte Chemie

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Structural studies of the 3′‐end of the oncogenic long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple‐helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA‐binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA‐focused libraries can generate insights into selective RNA recognition.

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“…Recently, Morgan et al delved into understanding the physicochemical, structural, and spatial properties of RNA ligands and compiled the RNA-targeted BIoactive ligaNd Database (R-BIND), which contains a list of bioactive monovalent small molecules and multivalent ligands that target non-ribosomal RNAs. 169,170 The overall aim of this database is to use 20 cheminformatic parameters, e.g. oral availability, Lipinski's rules, Veber's rules, structural components, molecular complexity, and molecular recognition, to determine trends in bioactive RNA ligands.…”

Section: Identification Of Rna-specific Small Molecule Therapeuticsmentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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

Cited by 100 publications

References 50 publications

Insights into the development of chemical probes for RNA

Insights into the development of chemical probes for RNA

Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold

Unveiling the druggable RNA targets and small molecule therapeutics

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