High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on recombinant CYP2D6 and CYP3A4 using a single concentration method

Xenobiotica ◽  
2004 ◽  
Vol 34 (1) ◽  
pp. 87-101 ◽  
Author(s):  
T. Yamamoto ◽  
A. Suzuki ◽  
Y. Kohno
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Time Dependent ◽  
Drug Candidates ◽  
New Drug ◽  
Concentration Method

scholarly journals Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

2016 ◽  
pp. 1307 ◽  
Author(s):  
Venkata Pothineni ◽  
Dhananjay Wagh ◽  
Mustafeez Mujtaba Babar ◽  
Mohammed Inayathullah ◽  
David Solow-Cordero ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
High Throughput ◽  
High Throughput Screening ◽  
Drug Candidates ◽  
New Drug

scholarly journals Meeting Report: High-Throughput Technologies for In Vivo Imaging Agents

2005 ◽  
Vol 4 (2) ◽  
pp. 153535002005051 ◽  
Author(s):  
Robert J. Gillies ◽  
John M. Hoffman ◽  
Kit S. Lam ◽  
Anne E. Menkens ◽  
David R. Piwnica-Worms ◽  
...  
Keyword(s):  
High Throughput ◽  
In Vivo Imaging ◽  
High Throughput Screening ◽  
Imaging Agents ◽  
Meeting Report ◽  
Screening Methods ◽  
Pharmacological Properties ◽  
Drug Candidates ◽  
Good Imaging

Combinatorial chemistry and high-throughput screening have become standard tools for discovering new drug candidates with suitable pharmacological properties. Now, those same technologies are starting to be applied to the problem of discovering novel in vivo imaging agents. Important differences in the biological and pharmacological properties needed for imaging agents, compared to those for a therapeutic agent, require new screening methods that emphasize those characteristics, such as optimized residence time and tissue specificity, that make for a good imaging agent candidate.

scholarly journals Novel Whole-Cell Antibiotic Biosensors for Compound Discovery

2007 ◽  
Vol 73 (20) ◽  
pp. 6436-6443 ◽  
Author(s):  
Andreas Urban ◽  
Stefan Eckermann ◽  
Beate Fast ◽  
Susanne Metzger ◽  
Matthias Gehling ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
High Throughput ◽  
High Throughput Screening ◽  
Protein Biosynthesis ◽  
Firefly Luciferase ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Environmental Biology ◽  
Drug Candidates ◽  
Novel Drug

ABSTRACT Cells containing reporters which are specifically induced via selected promoters are used in pharmaceutical drug discovery and in environmental biology. They are used in screening for novel drug candidates and in the detection of bioactive compounds in environmental samples. In this study, we generated and validated a set of five Bacillus subtilis promoters fused to the firefly luciferase reporter gene suitable for cell-based screening, enabling the as yet most-comprehensive high-throughput diagnosis of antibiotic interference in the major biosynthetic pathways of bacteria: the biosynthesis of DNA by the yorB promoter, of RNA by the yvgS promoter, of proteins by the yheI promoter, of the cell wall by the ypuA promoter, and of fatty acids by the fabHB promoter. The reporter cells mainly represent novel antibiotic biosensors compatible with high-throughput screening. We validated the strains by developing screens with a set of 14,000 pure natural products, representing a source of highly diverse chemical entities, many of them with antibiotic activity (6% with anti-Bacillus subtilis activity of ≤25 μg/ml]). Our screening approach is exemplified by the discovery of classical and novel DNA synthesis and translation inhibitors. For instance, we show that the mechanistically underexplored antibiotic ferrimycin A1 selectively inhibits protein biosynthesis.

scholarly journals A Novel High-Throughput Screening Assay for Sickle Cell Disease Drug Discovery

2009 ◽  
Vol 14 (4) ◽  
pp. 330-336 ◽  
Author(s):  
Eszter Pais ◽  
John S. Cambridge ◽  
Cage S. Johnson ◽  
Herbert J. Meiselman ◽  
Timothy C. Fisher ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rapid Screening ◽  
Cell Disease ◽  
Screening Assay ◽  
Drug Candidates ◽  
Test Molecule ◽  
High Throughput Screening Assay

Although the pathophysiology and molecular basis of sickle cell disease (SCD) were described more than half a century ago, an effective and safe therapy is not yet available. This may be explained by the lack of a suitable high-throughput technique that allows rapid screening of thousands of compounds for their antisickling effect. The authors have thus developed a novel high-throughput screening (HTS) assay based on detecting the ability of red blood cells (RBC) to traverse a column of tightly packed Sephacryl chromatography beads. When deoxygenated, sickle RBC are rigid and remain on the top of the column. However, when deoxygenated and treated with an effective antisickling agent, erythrocytes move through the Sephacryl media and produce a red dot on the bottom of the assay tubes. This approach has been adapted to wells in a 384-well microplate. Results can be obtained by optical scanning: The size of the red dot is proportional to the antisickling effect of the test molecule. The new assay is simple, inexpensive, reproducible, requires no special reagents, and should be readily adaptable to robotic HTS systems. It has the potential to identify novel drug candidates, allowing the development of new therapeutic options for individuals affected with SCD. ( Journal of Biomolecular Screening. 2009:330-336)

scholarly journals High-Throughput Screening of Novel Peptide Inhibitors of an Integrin Receptor from the Hexapeptide Library by Using a Protein Microarray Chip

2004 ◽  
Vol 9 (8) ◽  
pp. 687-694 ◽  
Author(s):  
Yoonsuk Lee ◽  
Dong-Ku Kang ◽  
Soo-Ik Chang ◽  
Moon Hi Han ◽  
In-Cheol Kang
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Competitive Inhibition ◽  
Protein Microarray ◽  
Dependent Manner ◽  
High Throughput Analysis ◽  
Microarray Chip ◽  
New Drug

Protein microarray is an emerging technology that makes high-throughput analysis possible for protein-protein interactions and analysis of proteome and biomarkers in parallel. The authors investigated the application of a novel protein microarray chip, Proteo Chip, in new drug discovery. Integrin αvβ3 microarray immobilized on the Proteo Chip was employed to screen new active peptides against the integrin from multiple hexapeptide sublibraries of a positional scanning synthetic peptide combinatorial library (PS-SPCL). The integrin αvβ3-vitronectin interaction was successfully demonstrated on the integrin microarray in a dose-dependent manner andwas inhibited not only by the syntheticRGDpeptide but also by various integrin antagonists on the integrin microarray chip. Novel peptide ligands with high affinity to the integrin were also identified from the peptide libraries with this chip-based screening system by a competitive inhibition assay in a simultaneous and highthroughput fashion. The authors have confirmed antiangiogenic functions of the novel peptides thus screened through an in vitro and in vivo angiogenesis assay. These results provide evidence that the Proteo Chip is a promising tool for highthroughput screening of lead molecules in new drug development.

scholarly journals Searching for Chemokine Receptor Binding Antagonists by High Throughput Screening

1997 ◽  
Vol 2 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Geoffrey W. Mellor ◽  
Simon J. Fogarty ◽  
M. Shane O'Brien ◽  
Miles Congreve ◽  
Martyn N. Banks ◽  
...  
Keyword(s):  
Receptor Binding ◽  
High Throughput ◽  
Chemokine Receptor ◽  
Combinatorial Chemistry ◽  
High Throughput Screening ◽  
Biological Targets ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Selective Antagonists ◽  
Biological Sources

Identification of putative drug candidates by high throughput screening is assuming enormous importance within the pharmaceutical industry, driven by increasing numbers of valid therapeutic targets from both classical and molecular biological sources. Screening is an applied discipline that requires equipment and, more importantly, thinking that is fundamentally different from more traditional, lower throughput assay methodology. This article describes the process as applied to the discovery of selective antagonists of three chemokine receptor binding systems, from the original biological targets to chemically prosecutable lead compounds, which are currently being investigated using traditional medicinal and combinatorial chemistry methods.

scholarly journals Development of a Bioluminescent High-Throughput Screening Assay for Nicotinamide Mononucleotide Adenylyltransferase (NMNAT)

2019 ◽  
Vol 25 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Brad A. Haubrich ◽  
Chakk Ramesha ◽  
David C. Swinney
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Drug Target ◽  
Time Dependent ◽  
Screening Assay ◽  
Bioluminescent Assay ◽  
Nicotinamide Mononucleotide ◽  
High Throughput Screening Assay ◽  
Nicotinamide Mononucleotide Adenylyltransferase

Nicotinamide mononucleotide adenylyltransferase (NMNAT; EC 2.7.7.1) catalyzes the reversible production of NAD+ from NMN+ and ATP and is a potential drug target for cancer and neurodegenerative diseases. A sensitive bioluminescent assay format suitable to high-throughput screening (HTS) and mechanistic follow-up has not been reported and is of value to identify new modulators of NMNATs. To this end, we report the development of a bioluminescent assay using Photinus pyralis ATP-dependent luciferase and luciferin for NMNAT1 in a 384-well plate format. We also report a mechanistic follow-up paradigm using this format to determine time dependence and competition with substrates. The assay and follow-up paradigm were used to screen 912 compounds from the National Cancer Institute (NCI) Mechanistic Diversity Set II and the Approved Oncology Set VI against NMNAT1. Twenty inhibitors with greater than 35% inhibition at 20 µM were identified. The follow-up studies showed that seven actives were time-dependent inhibitors of NMNAT1. 2,3-Dibromo-1,4-naphthoquinone was the most potent, time-dependent inhibitor with IC50 values of 0.76 and 0.26 µM for inhibition of the forward and reverse reactions of the enzyme, respectively, and was shown to be NMN and ATP competitive. The bioluminescent NMNAT assay and mechanistic-follow-up will be of use to identify new modulators of NAD biosynthesis.

SuFEx-Enabled High-Throughput Medicinal Chemistry

2019 ◽  
Author(s):  
Seiya Kitamura ◽  
Qinheng Zheng ◽  
Jordan L. Woehl ◽  
angelo solan ◽  
Emily Chen ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Small Molecule ◽  
High Throughput ◽  
Cysteine Protease ◽  
High Throughput Screening ◽  
Medicinal Chemistry ◽  
Biologically Active ◽  
Drug Candidates ◽  
Biological Probes ◽  
Small Molecule Probes

<p>Optimization of small-molecule probes or drugs is a lengthy, challenging and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible SuFEx click chemistry. A modest high-throughput screening hit against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products directly screened to yield drug-like inhibitors with 300-fold higher potency. We showed that the improved molecule is drug-like and biologically active in a bacteria-host coculture. Since these reactions can be performed on a picomole scale to conserve reagents, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.</p>

High-Throughput Screening for Small-Molecule Adiponectin Secretion Modulators

2011 ◽  
Vol 16 (6) ◽  
pp. 628-636 ◽  
Author(s):  
Kyosuke Hino ◽  
Hidetaka Nagata ◽  
Manabu Shimonishi ◽  
Motoharu Ido
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Drug Candidates ◽  
Insulin Resistant ◽  
Therapeutic Benefits ◽  
Pparγ Agonists ◽  
Agonistic Activity

Adiponectin is an adipokine secreted by adipocytes and plays a role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. Several studies have shown that upregulation of adiponectin has a number of therapeutic benefits. Although peroxisome proliferator-activated receptor γ (PPARγ) agonists are known to increase adiponectin secretion both in cultured adipocytes and humans, they have several side effects, such as weight gain, congestive heart failure, and edema. Therefore, adiponectin secretion modulators that do not possess PPARγ agonistic activity seem to promising for a number of conditions. Here, the authors report on the development of a reporter-based high-throughput screening (HTS) assay using insulin-resistant-mimic 3T3-L1 adipocytes for discovery of adiponectin secretion modulators. They screened a library of approximately 100 000 small-molecule compounds using this model, performed several follow-up screens, and identified six hit compounds that increase adiponectin secretion without having PPARγ agonistic activity. These compounds may be useful drug candidates for diabetes, obesity, atherosclerosis, and other metabolic syndromes. This HTS assay might be applicable to screening for other adipokine modulators that can be useful for the treatment of other conditions.

scholarly journals Identification of Activators of Human Fumarate Hydratase by Quantitative High-Throughput Screening

2019 ◽  
Vol 25 (1) ◽  
pp. 43-56
Author(s):  
Hu Zhu ◽  
Olivia W. Lee ◽  
Pranav Shah ◽  
Ajit Jadhav ◽  
Xin Xu ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cell Cancer ◽  
Krebs Cycle ◽  
Fumarate Hydratase ◽  
Metabolic Enzyme ◽  
Oxidation Activity ◽  
Drug Candidates ◽  
Starting Point

Fumarate hydratase (FH) is a metabolic enzyme that is part of the Krebs cycle and reversibly catalyzes the hydration of fumarate to malate. Mutations of the FH gene have been associated with fumarate hydratase deficiency (FHD), hereditary leiomyomatosis and renal cell cancer (HLRCC), and other diseases. Currently, there are no high-quality small-molecule probes for studying human FH. To address this, we developed a quantitative high-throughput screening (qHTS) FH assay and screened a total of 57,037 compounds from in-house libraries in dose–response. While no inhibitors of FH were confirmed, a series of phenyl-pyrrolo-pyrimidine-diones were identified as activators of human FH. These compounds were not substrates of FH, were inactive in a malate dehydrogenase counterscreen, and showed no detectable reduction–oxidation activity. The binding of two compounds from the series to human FH was confirmed by microscale thermophoresis. The low hit rate in this screening campaign confirmed that FH is a “tough target” to modulate, and the small-molecule activators of human FH reported here may serve as a starting point for further optimization and development into cellular probes of human FH and potential drug candidates.

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