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.

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.

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.

scholarly journals Small Molecules Targeting Biological Clock; A Novel Prospective for Anti-Cancer Drugs

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4937
Author(s):  
Sadia Rahman ◽  
Karlo Wittine ◽  
Mirela Sedić ◽  
Elitza P. Markova-Car
Keyword(s):  
Circadian Rhythm ◽  
Small Molecules ◽  
Small Molecule ◽  
Environmental Conditions ◽  
Recent Progress ◽  
Biological Clock ◽  
New Drugs ◽  
Anti Cancer ◽  
Growing Body ◽  
Potential Use

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer.

scholarly journals Understanding the morphology of solution processed fullerene-free small molecule bulk heterojunction blends

2016 ◽  
Vol 18 (18) ◽  
pp. 12476-12485 ◽  
Author(s):  
Andrew Namepetra ◽  
Elizabeth Kitching ◽  
Ala'a F. Eftaiha ◽  
Ian G. Hill ◽  
Gregory C. Welch
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Bulk Heterojunction ◽  
Morphological Characteristics ◽  
Perylene Diimide ◽  
Processing Conditions ◽  
Solution Processed ◽  
The Impact

The impact of processing conditions on the morphological characteristics of bulk-heterojunction molecular blends prepared from small molecules based on diketopyrrolopyrrole (DPP) and perylene-diimide (PDI) chromophores have been investigated.

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.

scholarly journals Magic-angle spinning NMR spectroscopy provides insight into the impact of small molecule uptake by G-quartet hydrogels

2020 ◽  
Vol 1 (7) ◽  
pp. 2236-2247
Author(s):  
G. N. Manjunatha Reddy ◽  
Gretchen M. Peters ◽  
Ben P. Tatman ◽  
Teena S. Rajan ◽  
Si Min Kock ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Small Molecules ◽  
Small Molecule ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Local Structures ◽  
Angle Spinning ◽  
The Impact ◽  
Insight Into

Compositions, local structures and interactions of medicinally relevant small molecules added to G-quartet hydrogels are characterized using gel-state NMR spectroscopy.

scholarly journals Small molecule recognition of disease-relevant RNA structures

2020 ◽  
Vol 49 (19) ◽  
pp. 7167-7199 ◽  
Author(s):  
Samantha M. Meyer ◽  
Christopher C. Williams ◽  
Yoshihiro Akahori ◽  
Toru Tanaka ◽  
Haruo Aikawa ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structures ◽  
Drug Discovery And Development ◽  
New Frontier ◽  
Molecule Recognition

Targeting RNAs with small molecules, a new frontier in drug discovery and development.

scholarly journals Small Molecule Supplements Improve Cultured Megakaryocyte Polyploidization by Modulating Multiple Cell Cycle Regulators

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaojing Zou ◽  
Mingyi Qu ◽  
Fang Fang ◽  
Zeng Fan ◽  
Lin Chen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
Leukemia Cell ◽  
Culture Method ◽  
Cell Cycle Regulators ◽  
Rock Inhibitor ◽  
Surface Marker Expression ◽  
The Impact

Platelets (PLTs) are produced by megakaryocytes (MKs) that completed differentiation and endomitosis. Endomitosis is an important process in which the cell replicates its DNA without cytokinesis and develops highly polyploid MK. In this study, to gain a better PLTs production, four small molecules (Rho-Rock inhibitor (RRI), nicotinamide (NIC), Src inhibitor (SI), and Aurora B inhibitor (ABI)) and their combinations were surveyed as MK culture supplements for promoting polyploidization. Three leukemia cell lines as well as primary mononuclear cells were chosen in the function and mechanism studies of the small molecules. In an optimal culture method, cells were treated with different small molecules and their combinations. The impact of the small molecules on megakaryocytic surface marker expression, polyploidy, proliferation, and apoptosis was examined for the best MK polyploidization supplement. The elaborate analysis confirmed that the combination of SI and RRI together with our MK induction system might result in efficient ploidy promotion. Our experiments demonstrated that, besides direct downregulation on the expression of cytoskeleton protein actin, SI and RRI could significantly enhance the level of cyclins through the suppression of p53 and p21. The verified small molecule combination might be further used in the in vitro PLT manufacture and clinical applications.

scholarly journals Minimization of the Line Resistance Impact on Memdiode-Based Simulations of Multilayer Perceptron Arrays Applied to Pattern Recognition

2021 ◽  
Vol 11 (1) ◽  
pp. 9
Author(s):  
Fernando Leonel Aguirre ◽  
Nicolás M. Gomez ◽  
Sebastián Matías Pazos ◽  
Félix Palumbo ◽  
Jordi Suñé ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Ex Situ ◽  
Multilayer Perceptrons ◽  
Spice Simulation ◽  
Large Dataset ◽  
High Line ◽  
Calibration Algorithm ◽  
The Impact ◽  
Line Resistance

In this paper, we extend the application of the Quasi-Static Memdiode model to the realistic SPICE simulation of memristor-based single (SLPs) and multilayer perceptrons (MLPs) intended for large dataset pattern recognition. By considering ex-situ training and the classification of the hand-written characters of the MNIST database, we evaluate the degradation of the inference accuracy due to the interconnection resistances for MLPs involving up to three hidden neural layers. Two approaches to reduce the impact of the line resistance are considered and implemented in our simulations, they are the inclusion of an iterative calibration algorithm and the partitioning of the synaptic layers into smaller blocks. The obtained results indicate that MLPs are more sensitive to the line resistance effect than SLPs and that partitioning is the most effective way to minimize the impact of high line resistance values.

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