scholarly journals Selection of RNAs for Constructing “Lighting-UP” Biomolecular Switches in Response to Specific Small Molecules

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e60222 ◽  
Author(s):  
Tamaki Endoh ◽  
Naoki Sugimoto
Keyword(s):  
2015 ◽  
Vol 3 (5) ◽  
pp. 2012-2018 ◽  
Author(s):  
Jason A. Michel ◽  
William H. Morris III ◽  
Charles M. Lukehart

Shape selectivity between cubic and tetrahedral Pt colloidal nanocrystals is achieved simply by selection of [Pt(OH)6]2− or [PtI6]2−, respectively, as the Pt precursor in basic aqueous solutions.


2019 ◽  
Vol 12 (594) ◽  
pp. eaat9797 ◽  
Author(s):  
António J. M. Ribeiro ◽  
Sayoni Das ◽  
Natalie Dawson ◽  
Rossana Zaru ◽  
Sandra Orchard ◽  
...  

The 21st century is witnessing an explosive surge in our understanding of pseudoenzyme-driven regulatory mechanisms in biology. Pseudoenzymes are proteins that have sequence homology with enzyme families but that are proven or predicted to lack enzyme activity due to mutations in otherwise conserved catalytic amino acids. The best-studied pseudoenzymes are pseudokinases, although examples from other families are emerging at a rapid rate as experimental approaches catch up with an avalanche of freely available informatics data. Kingdom-wide analysis in prokaryotes, archaea and eukaryotes reveals that between 5 and 10% of proteins that make up enzyme families are pseudoenzymes, with notable expansions and contractions seemingly associated with specific signaling niches. Pseudoenzymes can allosterically activate canonical enzymes, act as scaffolds to control assembly of signaling complexes and their localization, serve as molecular switches, or regulate signaling networks through substrate or enzyme sequestration. Molecular analysis of pseudoenzymes is rapidly advancing knowledge of how they perform noncatalytic functions and is enabling the discovery of unexpected, and previously unappreciated, functions of their intensively studied enzyme counterparts. Notably, upon further examination, some pseudoenzymes have previously unknown enzymatic activities that could not have been predicted a priori. Pseudoenzymes can be targeted and manipulated by small molecules and therefore represent new therapeutic targets (or anti-targets, where intervention should be avoided) in various diseases. In this review, which brings together broad bioinformatics and cell signaling approaches in the field, we highlight a selection of findings relevant to a contemporary understanding of pseudoenzyme-based biology.


1974 ◽  
Vol 61 (2) ◽  
pp. 516-528 ◽  
Author(s):  
J. Wayne Rabalais ◽  
Thomas P. Debies ◽  
Jeffrey L. Berkosky ◽  
Jan‐Tsyu J. Huang ◽  
Frank O. Ellison

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0249841
Author(s):  
Ravindra Jadhav ◽  
Ricardo Gallardo-Macias ◽  
Gaurav Kumar ◽  
Samer S. Daher ◽  
Amit Kaushik ◽  
...  

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.


Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2615 ◽  
Author(s):  
Kwang-Eun Choi ◽  
Anand Balupuri ◽  
Nam Sook Kang

Human ether-a-go-go-related gene (hERG) potassium channel blockage by small molecules may cause severe cardiac side effects. Thus, it is crucial to screen compounds for activity on the hERG channels early in the drug discovery process. In this study, we collected 5299 hERG inhibitors with diverse chemical structures from a number of sources. Based on this dataset, we evaluated different machine learning (ML) and deep learning (DL) algorithms using various integer and binary type fingerprints. A training set of 3991 compounds was used to develop quantitative structure–activity relationship (QSAR) models. The performance of the developed models was evaluated using a test set of 998 compounds. Models were further validated using external set 1 (263 compounds) and external set 2 (47 compounds). Overall, models with integer type fingerprints showed better performance than models with no fingerprints, converted binary type fingerprints or original binary type fingerprints. Comparison of ML and DL algorithms revealed that integer type fingerprints are suitable for ML, whereas binary type fingerprints are suitable for DL. The outcomes of this study indicate that the rational selection of fingerprints is important for hERG blocker prediction.


Synthesis ◽  
2020 ◽  
Vol 52 (11) ◽  
pp. 1695-1706 ◽  
Author(s):  
Adam Nelson ◽  
Shiao Chow ◽  
Adam I. Green ◽  
Christopher Arter ◽  
Samuel Liver ◽  
...  

Metal-catalysed carbenoid chemistry can be exploited for the synthesis of diverse ranges of small molecules from α-diazo carbonyl compounds. In this paper, three synthetic approaches to α-diazo amides are described, and their scope and limitations are determined. On the basis of these synthetic studies, recommendations are provided to assist the selection of the most appropriate approach for specific classes of product. The availability of practical and efficient syntheses of diverse α-diazo acetamides is expected to facilitate the discovery of many different classes of bioactive small molecules.


Synlett ◽  
2020 ◽  
Vol 31 (12) ◽  
pp. 1182-1184 ◽  
Author(s):  
Joseph P. A. Harrity ◽  
Muhannad A. E. Al-Saedy

Imidazo[1,2-a]pyridines are an important class of heterocycles that are prevalent in many bioactive small molecules. We report the direct introduction of a broad selection of aromatic, heteroaromatic, or alkyl fragments connected by a thioether group into these important heterocycles by using readily prepared thiosulfate salts.


2019 ◽  
Vol 3 (1) ◽  
pp. 53-62
Author(s):  
Mathieu B. Poirier ◽  
Jeremiah Hadwen ◽  
Alex MacKenzie

Abstract Most monogenic disorders are caused by a pathologic deficit or excess of a single transcript and/or protein. Given that small molecules, including drugs, can affect levels of mRNA and protein, the pharmacologic normalization of such pathogenic dosage represents a possible therapeutic approach for such conditions. Here, we review the literature exploring pharmacologic modulation of mRNA and/or protein levels for disorders with paralogous modifier genes, for haploinsufficient disorders (insufficient gene-product), as well as toxic gain-of-function disorders (surplus or pathologic gene-product). We also discuss challenges facing the development of rare disease therapy by pharmacologic modulation of mRNA and protein. Finally, we lay out guiding principles for selection of disorders which may be amenable to this approach.


iScience ◽  
2020 ◽  
Vol 23 (6) ◽  
pp. 101197 ◽  
Author(s):  
Jia Xie ◽  
Shuyue Wang ◽  
Peixiang Ma ◽  
Fei Ma ◽  
Jie Li ◽  
...  

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