scholarly journals Identification of Inhibitors for MDM2 Ubiquitin Ligase Activity from Natural Product Extracts by a Novel High-Throughput Electrochemiluminescent Screen

2008 ◽  
Vol 13 (3) ◽  
pp. 229-237 ◽  
Author(s):  
Christy A. Sasiela ◽  
David H. Stewart ◽  
Jirouta Kitagaki ◽  
Yassamin J. Safiran ◽  
Yili Yang ◽  
...  
Keyword(s):  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Antimicrobial Drugs ◽  
Screening Programs ◽  
Lead Compounds ◽  
Ubiquitin Ligase Activity ◽  
Testing Complex ◽  
Induced Apoptosis ◽  
Potential Therapeutics

High-throughput screening technologies have revolutionized the manner in which potential therapeutics are identified. Although they are the source of lead compounds for ~65% of anticancer and antimicrobial drugs approved by the Food and Drug Administration between 1981 and 2002, natural products have largely been excluded from modern screening programs. This is due, at least in part, to the inherent difficulties in testing complex extract mixtures, which often contain nuisance compounds, in modern bioassay systems. In this article, the authors present a novel electrochemiluminescent assay system for inhibition of MDM2 activity that is suitable for testing natural product extracts in high-throughput screening systems. The assay was used to screen more than 144,000 natural product extracts. The authors identified 1 natural product, sempervirine, that inhibited MDM2 auto-ubiquitination, MDM2-mediated p53 degradation, and led to accumulation of p53 in cells. Sempervirine preferentially induced apoptosis in transformed cells expressing wild-type p53, suggesting that it could be a potential lead for anticancer therapeutics. ( Journal of Biomolecular Screening 2008:229-237)

The Search for Novel Human Pancreatic α-Amylase Inhibitors: High-Throughput Screening of Terrestrial and Marine Natural Product Extracts

ChemBioChem ◽  
2008 ◽  
Vol 9 (3) ◽  
pp. 433-438 ◽  
Author(s):  
Chris A. Tarling ◽  
Kate Woods ◽  
Ran Zhang ◽  
Harry C. Brastianos ◽  
Gary D. Brayer ◽  
...  
Keyword(s):  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Marine Natural Product ◽  
Amylase Inhibitors

scholarly journals Development of a Robust Cytopathic Effect-Based High-Throughput Screening Assay To Identify Novel Inhibitors of Dengue Virus

2012 ◽  
Vol 56 (6) ◽  
pp. 3399-3401 ◽  
Author(s):  
Kevin D. McCormick ◽  
Shufeng Liu ◽  
Jana L. Jacobs ◽  
Ernesto T. A. Marques ◽  
Nicolas Sluis-Cremer ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cytopathic Effect ◽  
Complex Molecule ◽  
Denv Infection ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Natural Product Library

ABSTRACTWe have developed a robust cytopathic effect-based high-throughput screening assay to identify inhibitors of dengue virus (DENV) infection. Screening of a small natural product library yielded 11 hits. Four of these were found to be potent inhibitors of DENV, although serotype differences were noted. Taken together, these data suggest that screening of larger and more complex molecule libraries may result in the identification of more potent and specific DENV inhibitors.

Logistic Considerations to Deliver Natural Product Libraries for High-­Throughput Screening

2015 ◽  
pp. 91-104
Author(s):  
Ngoc Pham ◽  
Stephen Toms ◽  
David Camp ◽  
Ronald Quinn
Keyword(s):  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening

scholarly journals Drug discovery from Nature: automated high-quality sample preparation

2000 ◽  
Vol 22 (5) ◽  
pp. 149-157 ◽  
Author(s):  
Ralf Thiericke
Keyword(s):  
Drug Discovery ◽  
Sample Preparation ◽  
High Throughput ◽  
High Throughput Screening ◽  
Solid Phase ◽  
Structural Diversity ◽  
Synthetic Compound ◽  
Natural Origin ◽  
Screening Programs ◽  
Compound Libraries

Secondary metabolites from plants, animals and microorganisms have been proven to be an outstanding source for new and innovative drugs and show a striking structural diversity that supplements chemically synthesized compounds or libraries in drug discovery programs. Unfortunately, extracts from natural sources are usually complex mixtures of compounds:: often generated in time consuming and for the most part manual processes. As quality and quantity of the provided samples play a pivotal role in the success of high-throughput screening programs this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of a modified Zymark RapidTrace®SPE workstation an easy-to-handle and effective fractionation method has been developed which allows the generation of highquality samples from natural origin, fulfilling the requirements of an integration into high-throughput screening programs.

scholarly journals A Novel High-Throughput Technique for Identifying Monoclonal Antibodies capable of Death Receptor Induced Apoptosis

2009 ◽  
Vol 2 ◽  
pp. JCD.S3660
Author(s):  
Hang Fai Kwok ◽  
Julie A. Gormley ◽  
Christopher J. Scott ◽  
James A. Johnston ◽  
Shane A. Olwill
Keyword(s):  
Cell Death ◽  
High Throughput ◽  
High Throughput Screening ◽  
False Negative ◽  
Death Receptor ◽  
Annexin V ◽  
Fas Receptor ◽  
Induced Apoptosis

The study of death receptor family induced apoptosis has gained momentum in recent years with the knowledge that therapeutic antibodies targeting DR4 and DR5 (death receptor's 4 and 5) have proved efficacious in multiple clinical trials. The therapeutic rationale is based on targeting and amplifying a tumour tissues normal cell death programme (apoptosis). While advances in the targeting of DR4 and DR5 have been successful the search for an agonistic antibody to another family member, the Fas receptor, has proven more elusive. This is partly due to the differing in vitro and in vivo characteristics of individual antibodies. In order to induce Fas targeted cell death an antibody must be capable of binding to and trimerising the receptor. It has been shown that antibodies capable of performing this function in vivo, with the assistance of tumour associated cells, do not always induce apoptosis in vitro. As a result the use of current methodologies to detect functional antibodies in vitro may have dismissed potential therapeutic candidates ('false negative'). Here we report a novel high throughput screening technique which artificially cross-links antibodies bound to the Fas receptor. By combining this process with Annexin-V and Prodidium Iodide (PI) staining we can select for antibodies which have the potential to induce apoptosis in vivo.

Sensitivity of neuroprogenitor cells to chemical-induced apoptosis using a multiplexed assay suitable for high-throughput screening

Toxicology ◽  
2015 ◽  
Vol 333 ◽  
pp. 14-24 ◽  
Author(s):  
Ingrid Druwe ◽  
Theresa M. Freudenrich ◽  
Kathleen Wallace ◽  
Timothy J. Shafer ◽  
William R. Mundy
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Induced Apoptosis

scholarly journals High-Throughput Screening Platform for Natural Product–Based Drug Discovery Against 3 Neglected Tropical Diseases

2014 ◽  
Vol 20 (1) ◽  
pp. 82-91 ◽  
Author(s):  
F. Annang ◽  
G. Pérez-Moreno ◽  
R. García-Hernández ◽  
C. Cordon-Obras ◽  
J. Martín ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Neglected Tropical Diseases ◽  
Chemical Diversity ◽  
Tropical Diseases ◽  
Isolation And Characterization ◽  
Microbial Extracts

African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and target-based approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes. Natural products, in contrast, are a highly underexplored pool of unique chemical diversity that can serve as excellent templates for the synthesis of novel, biologically active molecules. We report here a validated HTS platform for the screening of microbial extracts against the 3 diseases. We have used this platform in a pilot project to screen a subset (5976) of microbial extracts from the MEDINA Natural Products library. Tandem liquid chromatography–mass spectrometry showed that 48 extracts contain potentially new compounds that are currently undergoing de-replication for future isolation and characterization. Known active components included actinomycin D, bafilomycin B1, chromomycin A3, echinomycin, hygrolidin, and nonactins, among others. The report here is, to our knowledge, the first HTS of microbial natural product extracts against the above-mentioned kinetoplastid parasites.

scholarly journals High-throughput screening for modulators ofACVR1transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva

2016 ◽  
Vol 9 (6) ◽  
pp. 685-696 ◽  
Author(s):  
Serena Cappato ◽  
Laura Tonachini ◽  
Francesca Giacopelli ◽  
Mario Tirone ◽  
Luis J. V. Galietta ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Potential Therapeutics

High-Throughput siRNA-Based Functional Target Validation

2004 ◽  
Vol 9 (4) ◽  
pp. 286-293 ◽  
Author(s):  
Hong Xin ◽  
Alejandro Bernal ◽  
Frank A. Amato ◽  
Albert Pinhasov ◽  
Jack Kauffman ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Target Genes ◽  
Discovery Process ◽  
Target Validation ◽  
Drug Discovery Process ◽  
Functional Identification ◽  
Screening Process ◽  
Lead Compounds

The drug discovery process pursued by major pharmaceutical companies for many years starts with target identification followed by high-throughput screening (HTS) with the goal of identifying lead compounds. To accomplish this goal, significant resources are invested into automation of the screening process or HTS. Robotic systems capable of handling thousands of data points per day are implemented across the pharmaceutical sector. Many of these systems are amenable to handling cell-based screening protocols as well. On the other hand, as companies strive to develop innovative products based on novel mechanisms of action(s), one of the current bottlenecks of the industry is the target validation process. Traditionally, bioinformatics and HTS groups operate separately at different stages of the drug discovery process. The authors describe the convergence and integration of HTS and bioinformatics to perform high-throughput target functional identification and validation. As an example of this approach, they initiated a project with a functional cell-based screen for a biological process of interest using libraries of small interfering RNA (siRNA) molecules. In this protocol, siRNAs function as potent gene-specific inhibitors. siRNA-mediated knockdown of the target genes is confirmed by TaqMan analysis, and genes with impacts on biological functions of interest are selected for further analysis. Once the genes are confirmed and further validated, they may be used for HTS to yield lead compounds.

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