scholarly journals High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1

2009 ◽  
Vol 76 (5) ◽  
pp. 1094-1103 ◽  
Author(s):  
L. Michelle Lewis ◽  
Gautam Bhave ◽  
Brian A. Chauder ◽  
Sreedatta Banerjee ◽  
Katharina A. Lornsen ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals A Novel Dengue Virus Inhibitor, BP13944, Discovered by High-Throughput Screening with Dengue Virus Replicon Cells Selects for Resistance in the Viral NS2B/NS3 Protease

2013 ◽  
Vol 58 (1) ◽  
pp. 110-119 ◽  
Author(s):  
Chi-Chen Yang ◽  
Han-Shu Hu ◽  
Ren-Huang Wu ◽  
Szu-Huei Wu ◽  
Shiow-Ju Lee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitor ◽  
Current Treatment ◽  
Stable Cell Line ◽  
Epidemic Disease ◽  
Molecule Inhibitor ◽  
Ns3 Protease

ABSTRACTDengue virus (DENV) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. No effective DENV vaccine is available, and the current treatment is only supportive. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified a potential small-molecule inhibitor, BP13944, via high-throughput screening (HTS) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of DENV serotype 2 (DENV-2). BP13944 reduced the expression of the DENV replicon reporter in cells, showing a 50% effective concentration (EC50) of 1.03 ± 0.09 μM. Without detectable cytotoxicity, the compound inhibited replication or viral RNA synthesis in all four serotypes of DENV but not in Japanese encephalitis virus (JEV). Sequencing analyses of several individual clones derived from BP13944-resistant RNAs purified from cells harboring the DENV-2 replicon revealed a consensus amino acid substitution (E66G) in the region of the NS3 protease domain. Introduction of E66G into the DENV replicon, an infectious DENV cDNA clone, and recombinant NS2B/NS3 protease constructs conferred 15.2-, 17.2-, and 3.1-fold resistance to BP13944, respectively. Our results identify an effective small-molecule inhibitor, BP13944, which likely targets the DENV NS3 protease. BP13944 could be considered part of a more effective treatment regime for inhibiting DENV in the future.

Necrosulfonamide inhibits necroptosis by selectively targeting the mixed lineage kinase domain-like protein

MedChemComm ◽  
2014 ◽  
Vol 5 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Daohong Liao ◽  
Liming Sun ◽  
Weilong Liu ◽  
Sudan He ◽  
Xiaodong Wang ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Kinase Domain ◽  
Small Molecule Inhibitor ◽  
Mixed Lineage Kinase ◽  
Sar Studies ◽  
Structure Activity ◽  
Molecule Inhibitor ◽  
Smac Mimetic

Through high-throughput screening of 200 000 compounds and subsequent structure–activity relationship (SAR) studies we identified necrosulfonamide (NSA) as a potent small molecule inhibitor for necroptosis, induced by a combination of TNF-a, Smac mimetic, and z-VAD-fmk (T/S/Z).

scholarly journals Bioactive recombinant human oncostatin M for NMR-based screening in drug discovery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Olga A. Mass ◽  
Joseph Tuccinardi ◽  
Luke Woodbury ◽  
Cody L. Wolf ◽  
Bri Grantham ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cancer Progression ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Inflammatory Diseases ◽  
Small Molecule Inhibitor ◽  
Oncostatin M ◽  
Nmr Studies ◽  
Molecule Inhibitor ◽  
Stat3 Phosphorylation

AbstractOncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded 1H, 15N HSQC NMR spectra with intense, well-dispersed peaks. Titration of 15N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 μM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening.

scholarly journals Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel

2010 ◽  
Vol 79 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Gautam Bhave ◽  
Brian A. Chauder ◽  
Wen Liu ◽  
Eric S. Dawson ◽  
Rishin Kadakia ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor
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