Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Hypnotics with novel modes of action.

ABSTRACT: Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABA_A receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug-drug interactions with e.g. alcohol, less memory impairment and dependence potential compared to classical hypnotics.

SUBMITTER: Hoyer D

PROVIDER: S-EPMC7015741 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Hypnotics with novel modes of action.

Hoyer Daniel D Allen Andrew A Jacobson Laura H LH

British journal of clinical pharmacology 20200117 2

Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABA<sub>A</sub> receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug-d ...[more]

PMID: 31756268

Similar Datasets

Towards novel herbicide modes of action by inhibiting lysine biosynthesis in plants.

Project description:Weeds are becoming increasingly resistant to our current herbicides, posing a significant threat to agricultural production. Therefore, new herbicides with novel modes of action are urgently needed. In this study, we exploited a novel herbicide target, dihydrodipicolinate synthase (DHDPS), which catalyses the first and rate-limiting step in lysine biosynthesis. The first class of plant DHDPS inhibitors with micromolar potency against Arabidopsis thaliana DHDPS was identified using a high-throughput chemical screen. We determined that this class of inhibitors binds to a novel and unexplored pocket within DHDPS, which is highly conserved across plant species. The inhibitors also attenuated the germination and growth of A. thaliana seedlings and confirmed their pre-emergence herbicidal activity in soil-grown plants. These results provide proof-of-concept that lysine biosynthesis represents a promising target for the development of herbicides with a novel mode of action to tackle the global rise of herbicide-resistant weeds.

| S-EPMC8341977 | biostudies-literature

Boolean modeling of transcriptome data reveals novel modes of heterotrimeric G-protein action.

Project description:Heterotrimeric G-proteins mediate crucial and diverse signaling pathways in eukaryotes. Here, we generate and analyze microarray data from guard cells and leaves of G-protein subunit mutants of the model plant Arabidopsis thaliana, with or without treatment with the stress hormone, abscisic acid. Although G-protein control of the transcriptome has received little attention to date in any system, transcriptome analysis allows us to search for potentially uncommon yet significant signaling mechanisms. We describe the theoretical Boolean mechanisms of G-protein x hormone regulation, and then apply a pattern matching approach to associate gene expression profiles with Boolean models. We find that (1) classical mechanisms of G-protein signaling are well represented. Conversely, some theoretical regulatory modes of the G-protein are not supported; (2) a new mechanism of G-protein signaling is revealed, in which Gbeta regulates gene expression identically in the presence or absence of Galpha; (3) guard cells and leaves favor different G-protein modes in transcriptome regulation, supporting system specificity of G-protein signaling. Our method holds significant promise for analyzing analogous 'switch-like' signal transduction events in any organism.

| S-EPMC2913393 | biostudies-literature

Spider Venom: Components, Modes of Action, and Novel Strategies in Transcriptomic and Proteomic Analyses.

Project description:This review gives an overview on the development of research on spider venoms with a focus on structure and function of venom components and techniques of analysis. Major venom component groups are small molecular mass compounds, antimicrobial (also called cytolytic, or cationic) peptides (only in some spider families), cysteine-rich (neurotoxic) peptides, and enzymes and proteins. Cysteine-rich peptides are reviewed with respect to various structural motifs, their targets (ion channels, membrane receptors), nomenclature, and molecular binding. We further describe the latest findings concerning the maturation of antimicrobial, and cysteine-rich peptides that are in most known cases expressed as propeptide-containing precursors. Today, venom research, increasingly employs transcriptomic and mass spectrometric techniques. Pros and cons of venom gland transcriptome analysis with Sanger, 454, and Illumina sequencing are discussed and an overview on so far published transcriptome studies is given. In this respect, we also discuss the only recently described cross contamination arising from multiplexing in Illumina sequencing and its possible impacts on venom studies. High throughput mass spectrometric analysis of venom proteomes (bottom-up, top-down) are reviewed.

| S-EPMC6832493 | biostudies-literature

Emerging modes-of-action in drug discovery.

Project description:An increasing focus on complex biology to cure diseases rather than merely treat symptoms has transformed how drug discovery can be approached. Instead of activating or blocking protein function, a growing repertoire of drug modalities can be leveraged or engineered to hijack cellular processes, such as translational regulation or degradation mechanisms. Drug hunters can therefore access a wider arsenal of modes-of-action to modulate biological processes and this review summarises these emerging strategies by highlighting the most representative examples of these approaches.

| S-EPMC6786009 | biostudies-literature

Untargeted Metabolomics To Ascertain Antibiotic Modes of Action.

Project description:Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.

| S-EPMC4808186 | biostudies-literature

Chemotype-selective modes of action of ?-opioid receptor agonists.

Project description:The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the ?-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays, and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A(1-17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes, which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR and suggest that "functional" residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation.

| S-EPMC3843062 | biostudies-literature

The Modes of Action of MARTX Toxin Effector Domains.

Project description:Many Gram-negative bacterial pathogens directly deliver numerous effector proteins from the bacterium to the host cell, thereby altering the target cell physiology. The already well-characterized effector delivery systems are type III, type IV, and type VI secretion systems. Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are another effector delivery platform employed by some genera of Gram-negative bacteria. These single polypeptide exotoxins possess up to five effector domains in a modular fashion in their central regions. Upon binding to the host cell plasma membrane, MARTX toxins form a pore using amino- and carboxyl-terminal repeat-containing arms and translocate the effector domains into the cells. Consequently, MARTX toxins affect the integrity of the host cells and often induce cell death. Thus, they have been characterized as crucial virulence factors of certain human pathogens. This review covers how each of the MARTX toxin effector domains exhibits cytopathic and/or cytotoxic activities in cells, with their structural features revealed recently. In addition, future directions for the comprehensive understanding of MARTX toxin-mediated pathogenesis are discussed.

| S-EPMC6315884 | biostudies-literature

Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes.

Project description:Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity, this class of carcinogens will not be detected. Therefore, alternative test are urgently needed. Non-genotoxic carcinogens, however, act through different modes of action, which complicates the development of such an assay. The aim of this study was to investigate whether gene expression profiling in primary mouse hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. Primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. To recognize similarities in mode of action at the transcriptomic level, both a supervised and an unsupervised comparison approach was applied.

2012-06-25 | E-GEOD-35058 | biostudies-arrayexpress

Characterization, modes of action, and application of a novel broad-spectrum bacteriocin BM1300 produced by Lactobacillus crustorum MN047.

Project description:Bacteriocins are ribosomally synthesized peptides with antibacterial activity against food-borne pathogenic bacteria that cause spoilage, possessing important potential for use as a natural preservative in the food industry. The novel bacteriocin BM1300 produced by Lactobacillus crustorum MN047 was identified after purification in this study. It displayed broad-spectrum antibacterial activity against some selected Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration (MIC) values of BM1300 against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 were 13.4 μg/mL and 6.7 μg/mL, respectively. Moreover, BM1300 showed excellent thermal (between 60 and 120 °C), pH (2-11), and chemical (Tween-40, Tween-80, Triton X-100, and EDTA) stabilities. Time-kill curves revealed that BM1300 exhibited bactericidal activity against S. aureus and E. coli. The scanning and transmission electron microscopy indicated that BM1300 acted by disrupting the cell membrane integrity and increasing cell membrane permeabilization of indicator bacteria. The disruption of cell membrane integrity caused by BM1300 was further demonstrated by the uptake of propidium iodide (PI) and the release of intracellular lactate dehydrogenase (LDH) and nucleic acid and proteins. Moreover, BM1300 affected cell cycle distribution to exert antibacterial activity collaboratively. Meanwhile, BM1300 inhibited the growth of S. aureus and E. coli of beef meat and improved the microbiological quality of beef meat. These findings place BM1300 as a potential biopreservative in the food industry.

| S-EPMC7688877 | biostudies-literature

Spirofused tetrahydroisoquinoline-oxindole hybrids as a novel class of fast acting antimalarial agents with multiple modes of action.

Project description:Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3',4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline-oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3'4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.

| S-EPMC7578093 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data