A catecholamine in which C-1 of the aminoethyl side-chain is hydroxy-substituted.
ChEBI ID: 33569
There are 2 compounds belonging to this class, involving 113 studies.
| Member | Definition | Role |
|---|---|---|
| (S)-noradrenaline | The S-enantiomer of noradrenaline. | |
| norepinephrine | The R-enantiomer of noradrenaline. | neurotransmitter; vasoconstrictor agent; alpha-adrenergic agonist; sympathomimetic agent; mouse metabolite |
| Pre-1990 | 1990-2000 | 2001-2010 | 2011-2020 | Post-2020 |
|---|---|---|---|---|
| 26 | 30 | 23 | 30 | 2 |
| Article |
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A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome.
Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions. |
Selective Discovery of GPCR Ligands within DNA-Encoded Chemical Libraries Derived from Natural Products: A Case Study on Antagonists of Angiotensin II Type I Receptor.
Natural products have failed to meet the urgent need for drug discovery in recent decades due to limited resources, necessitating new strategies for re-establishing the key role of natural products in hit screening. This work introduced DNA-encoding techniques into the synthesis of phenolic acid-focused libraries containing 32 000 diverse compounds. Online selection of the library using immobilized angiotensin II type I receptor (AT |
Retrospective assessment of rat liver microsomal stability at NCATS: data and QSAR models.
Hepatic metabolic stability is a key pharmacokinetic parameter in drug discovery. Metabolic stability is usually assessed in microsomal fractions and only the best compounds progress in the drug discovery process. A high-throughput single time point substrate depletion assay in rat liver microsomes (RLM) is employed at the National Center for Advancing Translational Sciences. Between 2012 and 2020, RLM stability data was generated for ~ 24,000 compounds from more than 250 projects that cover a wide range of pharmacological targets and cellular pathways. Although a crucial endpoint, little or no data exists in the public domain. In this study, computational models were developed for predicting RLM stability using different machine learning methods. In addition, a retrospective time-split validation was performed, and local models were built for projects that performed poorly with global models. Further analysis revealed inherent medicinal chemistry knowledge potentially useful to chemists in the pursuit of synthesizing metabolically stable compounds. In addition, we deposited experimental data for ~ 2500 compounds in the PubChem bioassay database (AID: 1508591). The global prediction models are made publicly accessible ( https://opendata.ncats.nih.gov/adme ). This is to the best of our knowledge, the first publicly available RLM prediction model built using high-quality data generated at a single laboratory. |
Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.
When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection. |
High-Throughput Screening to Identify Inhibitors of the Type I Interferon-Major Histocompatibility Complex Class I Pathway in Skeletal Muscle.
Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows that the pro-inflammatory type I interferons (IFN) and a downstream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high-throughput screening on >4500 compounds, including all approved drugs, through a series of cell-based assays to identify those that inhibit the type I IFN-MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblasts containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors, with the most potent being ruxolitinib, and epigenetic/transcriptional modulators like histone deacetylase inhibitors and the hypoxia-inducible factor 1 inhibitor echinomycin. Testing in animal models and clinical trials is necessary to translate these therapies to myositis patients. These robust assay technologies can be further utilized to interrogate the basic mechanisms of the type I IFN-MHC class I pathway, identify novel molecular probes, and elucidate possible environmental triggers that may lead to myositis. |
A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit both brain penetration and oral bioavailability of many chemotherapy drugs. Although US Food and Drug Administration guidelines require that potential interactions of investigational drugs with P-gp be explored, often this information does not enter the literature. In response, we developed a high-throughput screen to identify substrates of P-gp from a series of chemical libraries, testing a total of 10,804 compounds, most of which have known mechanisms of action. We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected subline KB-8-5-11 that overexpresses P-gp. KB-8-5-11 cells were also tested in the presence of a P-gp inhibitor (tariquidar) to assess reversibility of transporter-mediated resistance. Of the tested compounds, a total of 90 P-gp substrates were identified, including 55 newly identified compounds. Substrates were confirmed using an orthogonal killing assay against human embryonic kidney-293 cells overexpressing P-gp. We confirmed that AT7159 (cyclin-dependent kinase inhibitor), AT9283, (Janus kinase 2/3 inhibitor), ispinesib (kinesin spindle protein inhibitor), gedatolisib (PKI-587, phosphoinositide 3-kinase/mammalian target of rampamycin inhibitor), GSK-690693 (AKT inhibitor), and KW-2478 (heat-shock protein 90 inhibitor) were substrates. In addition, we assessed direct ATPase stimulation. ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693, and gedatolisib, whereas ispinesib, AT7519, and KW-2478 were weaker substrates. Combinations of P-gp substrates and inhibitors were assessed to demonstrate on-target synergistic cell killing. These data identified compounds whose oral bioavailability or brain penetration may be affected by P-gp. SIGNIFICANCE STATEMENT: The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to be expressed at barrier sites, where it acts to limit oral bioavailability and brain penetration of substrates. In order to identify novel compounds that are transported by P-gp, we developed a high-throughput screen using the KB-3-1 cancer cell line and its colchicine-selected subline KB-8-5-11. We screened the Mechanism Interrogation Plate (MIPE) library, the National Center for Advancing Translational Science (NCATS) pharmaceutical collection (NPC), the NCATS Pharmacologically Active Chemical Toolbox (NPACT), and a |
Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening.
Cell-based phenotypic screening is a commonly used approach to discover biological pathways, novel drug targets, chemical probes, and high-quality hit-to-lead molecules. Many hits identified from high-throughput screening campaigns are ruled out through a series of follow-up potency, selectivity/specificity, and cytotoxicity assays. Prioritization of molecules with little or no cytotoxicity for downstream evaluation can influence the future direction of projects, so cytotoxicity profiling of screening libraries at an early stage is essential for increasing the likelihood of candidate success. In this study, we assessed the cell-based cytotoxicity of nearly 10,000 compounds in the National Institutes of Health, National Center for Advancing Translational Sciences annotated libraries and more than 100,000 compounds in a diversity library against four normal cell lines (HEK 293, NIH 3T3, CRL-7250, and HaCat) and one cancer cell line (KB 3-1, a HeLa subline). This large-scale library profiling was analyzed for overall screening outcomes, hit rates, pan-activity, and selectivity. For the annotated library, we also examined the primary targets and mechanistic pathways regularly associated with cell death. To our knowledge, this is the first study to use high-throughput screening to profile a large screening collection (>100,000 compounds) for cytotoxicity in both normal and cancer cell lines. The results generated here constitute a valuable resource for the scientific community and provide insight into the extent of cytotoxic compounds in screening libraries, allowing for the identification and avoidance of compounds with cytotoxicity during high-throughput screening campaigns. |
Inhibition of natriuretic peptide receptor 1 reduces itch in mice.
There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch. |
Predictive models of aqueous solubility of organic compounds built on A large dataset of high integrity.
Aqueous solubility is one of the most important properties in drug discovery, as it has profound impact on various drug properties, including biological activity, pharmacokinetics (PK), toxicity, and in vivo efficacy. Both kinetic and thermodynamic solubilities are determined during different stages of drug discovery and development. Since kinetic solubility is more relevant in preclinical drug discovery research, especially during the structure optimization process, we have developed predictive models for kinetic solubility with in-house data generated from 11,780 compounds collected from over 200 NCATS intramural research projects. This represents one of the largest kinetic solubility datasets of high quality and integrity. Based on the customized atom type descriptors, the support vector classification (SVC) models were trained on 80% of the whole dataset, and exhibited high predictive performance for estimating the solubility of the remaining 20% compounds within the test set. The values of the area under the receiver operating characteristic curve (AUC-ROC) for the compounds in the test sets reached 0.93 and 0.91, when the threshold for insoluble compounds was set to 10 and 50 μg/mL respectively. The predictive models of aqueous solubility can be used to identify insoluble compounds in drug discovery pipeline, provide design ideas for improving solubility by analyzing the atom types associated with poor solubility and prioritize compound libraries to be purchased or synthesized. |
Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing.
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