A Fully Integrated High-Throughput Screening Methodology for the Discovery of New Polyolefin Catalysts:  Discovery of a New Class of High Temperature Single-Site Group (IV) Copolymerization Catalysts

2003 ◽  
Vol 125 (14) ◽  
pp. 4306-4317 ◽  
Author(s):  
Thomas R. Boussie ◽  
Gary M. Diamond ◽  
Christopher Goh ◽  
Keith A. Hall ◽  
Anne M. LaPointe ◽  
...  
Keyword(s):  
High Temperature ◽  
High Throughput ◽  
High Throughput Screening ◽  
Group Iv ◽  
Single Site ◽  
Fully Integrated ◽  
New Class ◽  
Site Group

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 716-724
Author(s):  
Yan A. Ivanenkov ◽  
Renat S. Yamidanov ◽  
Ilya A. Osterman ◽  
Petr V. Sergiev ◽  
Vladimir A. Aladinskiy ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Antibacterial Agents ◽  
Sos Response ◽  
Luciferase Assay ◽  
Translational Machinery ◽  
E Coli ◽  
New Class

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique. Methods: We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay. Results: In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment. Conclusion: The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

scholarly journals Targeting Quorum Sensing: High-Throughput Screening to Identify Novel LsrK Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3112 ◽  
Author(s):  
Viviana Gatta ◽  
Polina Ilina ◽  
Alison Porter ◽  
Stuart McElroy ◽  
Päivi Tammela
Keyword(s):  
Quorum Sensing ◽  
High Throughput ◽  
High Throughput Screening ◽  
Enteric Bacteria ◽  
New Class ◽  
Bacterial Pathogenicity ◽  
Autoinducer 2 ◽  
A Cell ◽  
The Moment ◽  
Antivirulence Agents

Since quorum sensing (QS) is linked to the establishment of bacterial infection, its inactivation represents one of the newest strategies to fight bacterial pathogens. LsrK is a kinase playing a key role in the processing of autoinducer-2 (AI-2), a quorum-sensing mediator in gut enteric bacteria. Inhibition of LsrK might thus impair the quorum-sensing cascade and consequently reduce bacterial pathogenicity. Aiming for the development of a target-based assay for the discovery of LsrK inhibitors, we evaluated different assay set-ups based on ATP detection and optimized an automation-compatible method for the high-throughput screening of chemical libraries. The assay was then used to perform the screening of a 2000-compound library, which provided 12 active compounds with an IC50 ≤ 10 µM confirming the effectiveness and sensitivity of our assay. Follow-up studies on the positive hits led to the identification of two compounds, harpagoside and rosolic acid, active in a cell-based AI-2 QS interference assay, which are at the moment the most promising candidates for the development of a new class of antivirulence agents based on LsrK inhibition.

Correlation of Optical and Automated Patch Clamp Electrophysiology for Identification of NaV1.7 Inhibitors

2020 ◽  
Vol 25 (5) ◽  
pp. 434-446
Author(s):  
Hongkang Zhang ◽  
Bryan D. Moyer ◽  
Violeta Yu ◽  
Joseph G. McGivern ◽  
Michael Jarosh ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
High Reliability ◽  
Selective Inhibitors ◽  
New Class ◽  
Random Library ◽  
Automated Patch Clamp ◽  
Patch Clamp Electrophysiology ◽  
Screening Platform ◽  
Subtype Selective

The voltage-gated sodium channel Nav1.7 is a genetically validated target for pain; pharmacological blockers are promising as a new class of nonaddictive therapeutics. The search for Nav1.7 subtype selective inhibitors requires a reliable, scalable, and sensitive assay. Previously, we developed an all-optical electrophysiology (Optopatch) Spiking HEK platform to study activity-dependent modulation of Nav1.7 in a format compatible with high-throughput screening. In this study, we benchmarked the Optopatch Spiking HEK assay with an existing validated automated electrophysiology assay on the IonWorks Barracuda (IWB) platform. In a pilot screen of 3520 compounds, which included compound plates from a random library as well as compound plates enriched for Nav1.7 inhibitors, the Optopatch Spiking HEK assay identified 174 hits, of which 143 were confirmed by IWB. The Optopatch Spiking HEK assay maintained the high reliability afforded by traditional fluorescent assays and further demonstrated comparable sensitivity to IWB measurements. We speculate that the Optopatch assay could provide an affordable high-throughput screening platform to identify novel Nav1.7 subtype selective inhibitors with diverse mechanisms of action, if coupled with a multiwell parallel optogenetic recording instrument.

scholarly journals High-Throughput Identification of Inhibitors of Human Mitochondrial Peptide Deformylase

2007 ◽  
Vol 12 (4) ◽  
pp. 521-535 ◽  
Author(s):  
Christophe Antczak ◽  
David Shum ◽  
Sindy Escobar ◽  
Bhramdeo Bassit ◽  
Earl Kim ◽  
...  
Keyword(s):  
High Throughput ◽  
Antiproliferative Activity ◽  
High Throughput Screening ◽  
Peptide Deformylase ◽  
Chemical Libraries ◽  
New Class ◽  
Cytotoxicity Studies ◽  
Antiproliferative Agent ◽  
And Performance

The human mitochondrial peptide deformylase (HsPDF) provides a potential new target for broadly acting antiproliferative agents. To identify novel nonpeptidomimetic and nonhydroxamic acid—based inhibitors of HsPDF, the authors have developed a high-throughput screening (HTS) strategy using a fluorescence polarization (FP)—based binding assay as the primary assay for screening chemical libraries, followed by an enzymatic-based assay to confirm hits, prior to characterization of their antiproliferative activity against established tumor cell lines. The authors present the results and performance of the established strategy tested in a pilot screen of 2880 compounds and the identification of the 1st inhibitors. Two common scaffolds were identified within the hits. Furthermore, cytotoxicity studies revealed that most of the confirmed hits have antiproliferative activity. These findings demonstrate that the designed strategy can identify novel functional inhibitors and provide a powerful alternative to the use of functional assays in HTS and support the hypothesis that HsPDF inhibitors may constitute a new class of antiproliferative agent. ( Journal of Biomolecular Screening 2007:521-535)

scholarly journals High-throughput design of high-performance lightweight high-entropy alloys

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rui Feng ◽  
Chuan Zhang ◽  
Michael C. Gao ◽  
Zongrui Pei ◽  
Fan Zhang ◽  
...  
Keyword(s):  
High Temperature ◽  
High Throughput ◽  
High Throughput Screening ◽  
Elevated Temperatures ◽  
Alloy System ◽  
Computational Method ◽  
High Entropy Alloy ◽  
High Entropy Alloys ◽  
Theoretical Understanding ◽  
High Entropy

AbstractDeveloping affordable and light high-temperature materials alternative to Ni-base superalloys has significantly increased the efforts in designing advanced ferritic superalloys. However, currently developed ferritic superalloys still exhibit low high-temperature strengths, which limits their usage. Here we use a CALPHAD-based high-throughput computational method to design light, strong, and low-cost high-entropy alloys for elevated-temperature applications. Through the high-throughput screening, precipitation-strengthened lightweight high-entropy alloys are discovered from thousands of initial compositions, which exhibit enhanced strengths compared to other counterparts at room and elevated temperatures. The experimental and theoretical understanding of both successful and failed cases in their strengthening mechanisms and order-disorder transitions further improves the accuracy of the thermodynamic database of the discovered alloy system. This study shows that integrating high-throughput screening, multiscale modeling, and experimental validation proves to be efficient and useful in accelerating the discovery of advanced precipitation-strengthened structural materials tuned by the high-entropy alloy concept.

scholarly journals High Throughput Screening Using Fully Integrated Robotic Screening

1997 ◽  
Vol 2 (3) ◽  
pp. 133-135 ◽  
Author(s):  
Martyn Banks ◽  
Alastair Binnie ◽  
Simon Fogarty
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Fully Integrated

scholarly journals Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening

2007 ◽  
Vol 17 (5) ◽  
pp. 1422-1427 ◽  
Author(s):  
Georgina A. Holloway ◽  
Jonathan B. Baell ◽  
Alan H. Fairlamb ◽  
Patrizia M. Novello ◽  
John P. Parisot ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Reductase Inhibitor ◽  
Trypanothione Reductase ◽  
New Class
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