RNALigands: a database and web server for RNA - ligand interactions

RNA ◽  
2021 ◽  
pp. rna.078889.121
Author(s):  
Saisai Sun ◽  
Jianyi Yang ◽  
Zhaolei Zhang
Keyword(s):  
Secondary Structure ◽  
Small Molecules ◽  
Small Molecule ◽  
Neurological Diseases ◽  
Experimental Studies ◽  
Rna Structures ◽  
Structural Motifs ◽  
Rna Molecules ◽  
Small Molecule Ligands ◽  
Ligand Interactions

Motivation: RNA molecules can fold into complex and stable 3-D structures, allowing them to carry out important genetic, structural, and regulatory roles inside the cell. These complex structures often contain 3-D pockets made up of secondary structural motifs that can be potentially targeted by small molecule ligands. Indeed, many RNA structures in PDB contain bound small molecules, and high-throughput experimental studies have generated large number of interacting RNA and ligand pairs. There are considerable interests in developing small molecule lead compounds targeting viral RNAs or those RNAs implicated in neurological diseases or cancer. Results: We hypothesize that RNAs that have similar secondary structural motifs may bind to similar small molecule ligands. Towards this goal, we established a database collecting RNA secondary structural motifs and bound small molecules ligands. We further developed a computational pipeline, which takes input an RNA sequence, predicts its secondary structure, extracts structural motifs and searches the database for similar secondary structure motifs and interacting small molecules. We demonstrated the utility of the server by querying α-synuclein mRNA 5′ UTR sequence and finding potential matches which was validated as correct. Availability and Implementation: The server is publicly available at http://RNALigands.ccbr.utoronto.ca. The source code can also be downloaded at https://github.com/SaisaiSun/RNALigands.

Quantitative Structure Activity Relationship (QSAR) study predicts small molecule binding to RNA structure

2021 ◽  
Author(s):  
Zhengguo Cai ◽  
Martina Zafferani ◽  
Olanrewaju Akande ◽  
Amanda Hargrove
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structure ◽  
Quantitative Structure ◽  
Rna Structures ◽  
Qsar Study ◽  
Structure Activity ◽  
Qsar Models ◽  
Hiv 1

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSAR). Herein, we developed QSAR models that quantitatively predict both thermodynamic and kinetic-based binding parameters of small molecules and the HIV-1 TAR model RNA system. A set of small molecules bearing diverse scaffolds was screened against the HIV-1-TAR construct using surface plasmon resonance, which provided the binding kinetics and affinities. The data was then analyzed using multiple linear regression (MLR) combined with feature selection to afford robust models for binding of diverse RNA-targeted scaffolds. The predictivity of the model was validated on untested small molecules. The QSAR models presented herein represent the first application of validated and predictive 2D-QSAR using multiple scaffolds against an RNA target. We expect the workflow to be generally applicable to other RNA structures, ultimately providing essential insight into the small molecule descriptors that drive selective binding interactions and, consequently, providing a platform that can exponentially increase the efficiency of ligand design and optimization without the need for high-resolution RNA structures.

Synthetic Small Molecules Targeting G-Quadruplexes and their Application

2015 ◽  
Vol 1088 ◽  
pp. 507-513
Author(s):  
Hui Yu ◽  
Yan Li Wang ◽  
Xiao Yin Zhao ◽  
Wen Zhang
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Mode ◽  
Current Understanding ◽  
Promising Target ◽  
G Quadruplex ◽  
Small Molecule Ligands

G-quadruplex is expected to be a promising target for drug design. The manually synthesized small-molecule compounds are able to induce the formation of and stabilize G-quadruplexes. In this paper, we summarize the current understanding of the structure of G-quadruplexes, the binding mode of G-quadruplexes and small-molecule ligands, and important synthesized small molecules targeting G-quadruplexes as potential drugs.

scholarly journals Development and Implementation of an HTS-Compatible Assay for the Discovery of Selective Small-Molecule Ligands for Pre-microRNAs

2017 ◽  
Vol 23 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Daniel A. Lorenz ◽  
Steve Vander Roest ◽  
Martha J. Larsen ◽  
Amanda L. Garner
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Two Dimensional ◽  
Small Molecule Ligands ◽  
Gene Regulatory ◽  
Regulatory Rnas ◽  
Target Rna

microRNAs (miRNAs) are small gene regulatory RNAs, and their expression has been found to be dysregulated in a number of human diseases. To facilitate the discovery of small molecules capable of selectively modulating the activity of a specific miRNA, we have utilized new high-throughput screening technology targeting Dicer-mediated pre-miRNA maturation. Pilot screening of ~50,000 small molecules and ~33,000 natural product extract libraries against pre-miR-21 processing indicated the potential of our assay for this goal, yielding a campaign Z′ factor of 0.52 and an average plate signal-to-background (S/B) ratio of 13. Using two-dimensional screening against a second pre-miRNA, pre-let-7d, we evaluated the selectivity of confirmed hits. The results presented demonstrate how high-throughput screening can be used to identify selective small molecules for a target RNA.

scholarly journals Target-Directed Approaches for Screening Small Molecules against RNA Targets

2020 ◽  
Vol 25 (8) ◽  
pp. 869-894 ◽  
Author(s):  
Hafeez S. Haniff ◽  
Laurent Knerr ◽  
Jonathan L. Chen ◽  
Matthew D. Disney ◽  
Helen L. Lightfoot
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Drug Targets ◽  
Industrial Development ◽  
Rna Binding ◽  
Cellular Functions ◽  
Rna Molecules ◽  
The Face ◽  
Rna Binders ◽  
The Right

RNA molecules have a variety of cellular functions that can drive disease pathologies. They are without a doubt one of the most intriguing yet controversial small-molecule drug targets. The ability to widely target RNA with small molecules could be revolutionary, once the right tools, assays, and targets are selected, thereby defining which biomolecules are targetable and what constitutes drug-like small molecules. Indeed, approaches developed over the past 5–10 years have changed the face of small molecule–RNA targeting by addressing historic concerns regarding affinity, selectivity, and structural dynamics. Presently, selective RNA–protein complex stabilizing drugs such as branaplam and risdiplam are in clinical trials for the modulation of SMN2 splicing, compounds identified from phenotypic screens with serendipitous outcomes. Fully developing RNA as a druggable target will require a target engagement-driven approach, and evolving chemical collections will be important for the industrial development of this class of target. In this review we discuss target-directed approaches that can be used to identify RNA-binding compounds and the chemical knowledge we have today of small-molecule RNA binders.

scholarly journals A systematic analysis of atomic protein–ligand interactions in the PDB

MedChemComm ◽  
2017 ◽  
Vol 8 (10) ◽  
pp. 1970-1981 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Matthieu Schapira
Keyword(s):  
Small Molecule ◽  
Interaction Type ◽  
Systematic Analysis ◽  
Protein Ligand Interactions ◽  
Atom Pairs ◽  
Atomic Interactions ◽  
Small Molecule Ligands ◽  
Ligand Interactions ◽  
The Impact ◽  
Protein Atom

We compiled a list of 11 016 unique structures of small-molecule ligands bound to proteins representing 750 873 protein–ligand atomic interactions, and analyzed the frequency, geometry and the impact of each interaction type. The most frequent ligand–protein atom pairs can be clustered into seven interaction types.

MALDI-TOF-Based Affinity Selection Mass Spectrometry for Automated Screening of Protein–Ligand Interactions at High Throughput

2020 ◽  
Vol 26 (1) ◽  
pp. 44-57
Author(s):  
Roman P. Simon ◽  
Martin Winter ◽  
Carola Kleiner ◽  
Lucie Wehrle ◽  
Michael Karnath ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Small Molecule ◽  
High Throughput ◽  
Binding Assay ◽  
Size Exclusion ◽  
Affinity Selection ◽  
Maldi Tof ◽  
Protein Ligand Interactions ◽  
Small Molecule Ligands ◽  
Ligand Interactions

Demonstration of in vitro target engagement for small-molecule ligands by measuring binding to a molecular target is an established approach in early drug discovery and a pivotal step in high-throughput screening (HTS)-based compound triaging. We describe the setup, evaluation, and application of a ligand binding assay platform combining automated affinity selection (AS)-based sample preparation and label-free matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. The platform enables mass spectrometry (MS)-based HTS for small-molecule target interactions from single-compound incubation mixtures and is embedded into a regular assay automation environment. Efficient separation of target–ligand complexes is achieved by in-plate size exclusion chromatography (SEC), and small-molecule ligands are subsequently identified by MALDI-TOF analysis. In contrast to alternative HTS-capable binding assay formats, MALDI-TOF AS-MS is capable of identifying orthosteric and allosteric ligands, as shown for the model system protein tyrosine phosphatase 1B (PTP1B), irrespective of protein function. Furthermore, determining relative binding affinities (RBAs) enabled ligand ranking in accordance with functional inhibition and reference data for PTP1B and a number of diverse protein targets. Finally, we present a validation screen of more than 23,000 compounds within 24 h, demonstrating the general applicability of the platform for the HTS-compatible assessment of protein–ligand interactions.

Assessing the feasibility and stability of uracil base flipping in RNA–small molecule complexes using molecular dynamics simulations

2020 ◽  
Vol 98 (6) ◽  
pp. 261-269
Author(s):  
Lauren D. Hagler ◽  
Sarah E. Bonson ◽  
Philip A. Kocheril ◽  
Steven C. Zimmerman
Keyword(s):  
Molecular Dynamics ◽  
Small Molecules ◽  
Molecular Dynamics Simulations ◽  
Small Molecule ◽  
Computational Study ◽  
Repeat Sequence ◽  
Base Flipping ◽  
Small Molecule Ligands ◽  
Dynamics Simulations ◽  
Rna Complexes

Small molecules can be used to target RNAs that mediate disease. A fundamental understanding of binding interactions between RNA and small molecules and the structure of their complexes will further inform the design of new targeting agents. Two small molecule ligands were investigated for their ability to recognize the expanded CUG repeat sequence in RNA, the causative agent of myotonic dystrophy type 1. We report the use of molecular dynamics simulations to explore small molecule–RNA complexes and the finding of a stabilized base flipped conformation at UU mismatches. The results of this computational study support experimental observations and suggest that base flipping is feasible for CUG-repeat RNA.

Sensing the impact of environment on small molecule differentiation of RNA sequences

2017 ◽  
Vol 53 (100) ◽  
pp. 13363-13366 ◽  
Author(s):  
Christopher S. Eubanks ◽  
Amanda E. Hargrove
Keyword(s):  
Pattern Recognition ◽  
Small Molecules ◽  
Small Molecule ◽  
Environmental Conditions ◽  
Rna Structures ◽  
Rna Sequences ◽  
The Impact

Pattern recognition of RNA with small molecules (PRRSM) reveals the impact of environmental conditions on the differentiation of RNA structures.

scholarly journals Conserved Structural Motifs of Two Distant IAV Subtypes in Genomic Segment 5 RNA

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 525
Author(s):  
Paula Michalak ◽  
Julita Piasecka ◽  
Barbara Szutkowska ◽  
Ryszard Kierzek ◽  
Ewa Biala ◽  
...  
Keyword(s):  
Experimental Data ◽  
Secondary Structure ◽  
Influenza A Virus ◽  
Influenza A ◽  
Chemical Mapping ◽  
Rna Structures ◽  
Structural Motifs ◽  
2009 H1n1

The functionality of RNA is fully dependent on its structure. For the influenza A virus (IAV), there are confirmed structural motifs mediating processes which are important for the viral replication cycle, including genome assembly and viral packaging. Although the RNA of strains originating from distant IAV subtypes might fold differently, some structural motifs are conserved, and thus, are functionally important. Nowadays, NGS-based structure modeling is a source of new in vivo data helping to understand RNA biology. However, for accurate modeling of in vivo RNA structures, these high-throughput methods should be supported with other analyses facilitating data interpretation. In vitro RNA structural models complement such approaches and offer RNA structures based on experimental data obtained in a simplified environment, which are needed for proper optimization and analysis. Herein, we present the secondary structure of the influenza A virus segment 5 vRNA of A/California/04/2009 (H1N1) strain, based on experimental data from DMS chemical mapping and SHAPE using NMIA, supported by base-pairing probability calculations and bioinformatic analyses. A comparison of the available vRNA5 structures among distant IAV strains revealed that a number of motifs present in the A/California/04/2009 (H1N1) vRNA5 model are highly conserved despite sequence differences, located within previously identified packaging signals, and the formation of which in in virio conditions has been confirmed. These results support functional roles of the RNA secondary structure motifs, which may serve as candidates for universal RNA-targeting inhibitory methods.

scholarly journals Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model

2019 ◽  
Vol 116 (16) ◽  
pp. 7799-7804 ◽  
Author(s):  
Alicia J. Angelbello ◽  
Suzanne G. Rzuczek ◽  
Kendra K. Mckee ◽  
Jonathan L. Chen ◽  
Hailey Olafson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Neuromuscular Disorder ◽  
Repeat Expansion ◽  
Rna Structures ◽  
Target Disease ◽  
Preclinical Animal Models

Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG)exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.

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