scholarly journals Bio-instructive materials on-demand – combinatorial chemistry of peptoids, foldamers, and beyond

2021 ◽  
Author(s):  
Claudine Herlan ◽  
Dominik Feser ◽  
Ute Schepers ◽  
Stefan Bräse
Keyword(s):  
High Throughput ◽  
Combinatorial Chemistry ◽  
Medicinal Chemistry ◽  
Materials Science ◽  
Modular Design ◽  
Rapid Synthesis ◽  
On Demand ◽  
Compound Libraries ◽  
Large Compound

Combinatorial chemistry allows for the rapid synthesis of large compound libraries for high throughput screenings in biology, medicinal chemistry, or materials science. Especially compounds from a highly modular design are...

scholarly journals A Direct-to-Biology High-Throughput Chemistry Approach to Reactive Fragment Screening

2021 ◽  
Author(s):  
Ross P. Thomas ◽  
Rachel E. Heap ◽  
Francesca Zappacosta ◽  
Emma K. Grant ◽  
Peter Pogany ◽  
...  
Keyword(s):  
High Throughput ◽  
Medicinal Chemistry ◽  
Binding Pocket ◽  
Rapid Identification ◽  
Rapid Synthesis ◽  
Iterative Design ◽  
Fragment Screening ◽  
Hit Rate ◽  
Chemical Tools ◽  
Screening Platform

<p>Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of <a>new medicines. Here, we report a screening platform that combines ‘direct-to-biology’ high-throughput chemistry (D2B-HTC) with photoreactive covalent fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates. Screening the HTC-PhABit library with </a>carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn<sup>2+</sup> binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design-make-test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource.</p>

scholarly journals Development and Validation of a High-Throughput Screen for Inhibitors of SARS CoV and Its Application in Screening of a 100,000-Compound Library

2006 ◽  
Vol 12 (1) ◽  
pp. 33-40 ◽  
Author(s):  
William E. Severson ◽  
Nice Shindo ◽  
Mindy Sosa ◽  
Thomas Fletcher ◽  
E. Lucile White ◽  
...  
Keyword(s):  
High Throughput ◽  
Cytopathic Effect ◽  
High Throughput Screen ◽  
Compound Library ◽  
Hit Rate ◽  
Compound Libraries ◽  
Potential Inhibitors ◽  
Development And Validation ◽  
Large Compound

The authors have developed a high-throughput screen (HTS) that allows for the identification of potential inhibitors of the severe acute respiratory syndrome coronavirus (SARS CoV) from large compound libraries. The luminescent-based assay measures the inhibition of SARS CoV–induced cytopathic effect (CPE) in Vero E6 cells. The assay was validated in 96-well plates in a BSL3 containment facility. The assay is sensitive and robust, with Z values > 0.6, signal to background (S/B) > 16, and signal to noise (S/N) > 3. The assay was further validated with 2 different diversity sets of compounds against the SARS CoV. The “hit” rate for both libraries was approximately 0.01%. The validated HTS assay was then employed to screen a 100,000-compound library against SARS CoV. The hit rate for the library in a single-dose format was determined to be approximately 0.8%. Screening of the 3 libraries resulted in the identification of several novel compounds that effectively inhibited the CPE of SARS CoV in vitro—compounds which will serve as excellent lead candidates for further evaluation. At a 10-μM concentration, 3 compounds with selective indexes (SI50) of > 53 were discovered.

scholarly journals A Direct-to-Biology High-Throughput Chemistry Approach to Reactive Fragment Screening

2021 ◽  
Author(s):  
Ross P. Thomas ◽  
Rachel E. Heap ◽  
Francesca Zappacosta ◽  
Emma K. Grant ◽  
Peter Pogany ◽  
...  
Keyword(s):  
High Throughput ◽  
Medicinal Chemistry ◽  
Binding Pocket ◽  
Rapid Identification ◽  
Rapid Synthesis ◽  
Iterative Design ◽  
Fragment Screening ◽  
Hit Rate ◽  
Chemical Tools ◽  
Screening Platform

<p>Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of <a>new medicines. Here, we report a screening platform that combines ‘direct-to-biology’ high-throughput chemistry (D2B-HTC) with photoreactive covalent fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates. Screening the HTC-PhABit library with </a>carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn<sup>2+</sup> binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design-make-test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource.</p>

scholarly journals Assay Miniaturization for Ultra-High Throughput Screening of Combinatorial and Discrete Compound Libraries: A 9600-Well (0.2 Microliter) Assay System

1998 ◽  
Vol 3 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Kevin R. Oldenburg ◽  
Ji-Hu Zhang ◽  
Tongming Chen ◽  
Anthony Maffia ◽  
Karl F. Blom ◽  
...  
Keyword(s):  
High Throughput ◽  
Combinatorial Chemistry ◽  
Therapeutic Target ◽  
High Throughput Screening ◽  
Detection System ◽  
Screening System ◽  
Handling System ◽  
Liquid Handling ◽  
Compound Libraries ◽  
Plate Design

Combinatorial chemistry has opened a new realm of chemical entities in the search for novel therapeutics. Combinatorial chemistry is currently adding hundreds of thousands of compounds to similar numbers available from years of synthesis by medicinal chemistry. It is not unreasonable to expect that over the next several years, nearly a million compounds will be available for screening against each therapeutic target. The number of potential targets will also be increasing with the advances in genomics. With the increasing number of compounds to be screened against an increasing number of targets, it is becoming increasingly difficult and costly to obtain the required amounts of key biological material needed to screen these compounds. One obvious solution is to miniaturize the assays so that the biological reagent supply doesn't need to increase. To this end, we have developed an ultra-high throughput screening system comprised of a new plate design (9600-well), detection system, and liquid handling system. This new format is capable of performing assays in as little as 0.2 Al. The results obtained from this system compare favorably to those obtained in the standard 96-well format.

scholarly journals High-Throughput Mass Spectrometry Screening for Inhibitors of Phosphatidylserine Decarboxylase

2007 ◽  
Vol 12 (5) ◽  
pp. 628-634 ◽  
Author(s):  
Chris D. Forbes ◽  
Joshuaine G. Toth ◽  
Can C. Özbal ◽  
William A. Lamarr ◽  
Jennifer A. Pendleton ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Catalytic Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Lipid Synthesis ◽  
High Quality ◽  
Compound Libraries ◽  
Z Value ◽  
Large Compound ◽  
Mass Spectrometry Assay

A high-throughput mass spectrometry assay to measure the catalytic activity of phosphatidylserine decarboxylase (PISD) is described. PISD converts phosphatidylserine to phosphatidylethanolamine during lipid synthesis. Traditional methods of measuring PISD activity are low throughput and unsuitable for the high-throughput screening of large compound libraries. The high-throughput mass spectrometry assay directly measures phosphatidylserine and phosphatidylethanolamine using the RapidFire™ platform at a rate of 1 sample every 7.5 s. The assay is robust, with an average Z′ value of 0.79 from a screen of 9920 compounds. Of 60 compounds selected for confirmation, 54 are active in dose-response studies. The application of high-throughput mass spectrometry permitted a high-quality screen to be performed for an otherwise intractable target. ( Journal of Biomolecular Screening 2007:628-634)

scholarly journals Stable Cell Clones Harboring Self-Replicating SARS-CoV-2 RNAs for Drug Screen

2021 ◽  
Author(s):  
Shufeng Liu ◽  
Chao-Kai Chou ◽  
Wells W Wu ◽  
Binquan Luan ◽  
Tony T Wang
Keyword(s):  
High Throughput ◽  
Structural Protein ◽  
Compound Libraries ◽  
Cell Clones ◽  
Replication Systems ◽  
Functional Analyses ◽  
High Throughput Screens ◽  
First Time ◽  
Large Compound ◽  
Level 2

The development of antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been hampered by the lack of efficient cell-based replication systems that are amenable to high-throughput screens in biosafety level 2 laboratories. Here we report that stable cell clones harboring autonomously replicating SARS-CoV-2 RNAs without S, M, E genes can be efficiently derived from the baby hamster kidney (BHK-21) cell line when a pair of mutations were introduced into the non-structural protein 1 (Nsp1) of SARS-CoV-2 to ameliorate cellular toxicity associated with virus replication. In a proof-of-concept experiment we screened a 273-compound library using replicon cells and identified three compounds as novel inhibitors of SARS-CoV-2 replication. Altogether, this work establishes a robust, cell-based system for genetic and functional analyses of SARS-CoV-2 replication and for the development of antiviral drugs. IMPORTANCE: SARS-CoV-2 replicon systems that have been reported up to date were unsuccessful in deriving stable cell lines harboring non-cytopathic replicons. The transient expression of viral sgmRNA or a reporter gene makes it impractical for industry-scale screening of large compound libraries using these systems. Here, for the first time, we derived stable cell clones harboring the SARS-CoV-2 replicon. These clones may now be conveniently cultured in a standard BSL-2 laboratory for high throughput screen of compound libraries. This achievement represents a ground-breaking discovery that will greatly accelerate the pace of developing treatments for COVID-19.

scholarly journals High-throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain

2021 ◽  
Author(s):  
Morgan A Dasovich ◽  
Junlin Zhou ◽  
Ajit G Thomas ◽  
Jack A Goodman ◽  
Robert Lyle McPherson ◽  
...  
Keyword(s):  
Antiviral Therapy ◽  
High Throughput ◽  
Activity Assay ◽  
Selective Inhibitors ◽  
Antiviral Therapies ◽  
Compound Libraries ◽  
Promising Target ◽  
High Throughput Assay ◽  
Large Compound ◽  
The Way

Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodo-main inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here, we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen which identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib does not inhibit MacroD2, the closest Mac1 homolog in humans. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for screening large compound libraries to identify improved macrodomain inhibitors and explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.

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