Using High-Throughput Screening Data To Discriminate Compounds with Single-Target Effects from Those with Side Effects

2006 ◽  
Vol 46 (4) ◽  
pp. 1549-1562 ◽  
Author(s):  
Justin Klekota ◽  
Erik Brauner ◽  
Frederick P. Roth ◽  
Stuart L. Schreiber
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Single Target ◽  
Target Effects

scholarly journals Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening

2017 ◽  
Vol 23 (4) ◽  
pp. 375-383 ◽  
Author(s):  
Lisa M. Ogawa ◽  
Neil T. Burford ◽  
Yu-Hsien Liao ◽  
Caitlin E. Scott ◽  
Ashley M. Hine ◽  
...  
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Immune Modulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Allosteric Modulators ◽  
Peripheral Tissues ◽  
Selective Agonists

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.

scholarly journals High-Throughput Screening for Positive Allosteric Modulators Identified Potential Therapeutics against Acetylcholinesterase Inhibition

2015 ◽  
Vol 20 (9) ◽  
pp. 1142-1149 ◽  
Author(s):  
Richard R. Chapleau ◽  
Craig A. McElroy ◽  
Christopher D. Ruark ◽  
Emily J. Fleming ◽  
Amy B. Ghering ◽  
...  
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Standard Of Care ◽  
Acetylcholinesterase Inhibition ◽  
Therapeutic Window ◽  
Ache Inhibitor ◽  
Allosteric Modulators ◽  
Current Standard ◽  
Positive Allosteric Modulators

The current standard of care for treatment of organophosphate (OP) poisoning includes pretreatment with the weak reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide. Because this drug is an AChE inhibitor, similar side effects exist as with OP poisoning. In an attempt to provide a therapeutic capable of mitigating AChE inhibition without such side effects, high-throughput screening was performed to identify a compound capable of increasing the catalytic activity of AChE. Herein, two such novel positive allosteric modulators (PAMs) of AChE are presented. These PAMs increase AChE activity threefold, but they fail to upshift the apparent IC50 of a variety of OPs. Further development and optimization of these compounds may lead to pre- and/or postexposure therapeutics with broad-spectrum efficacy against pesticide and nerve agent poisoning. In addition, they could be used to complement the current therapeutic standard of care to increase the activity of uninhibited AChE, potentially increasing the efficacy of current therapeutics in addition to altering the therapeutic window.

scholarly journals On-target activity predictions enable improved CRISPR–dCas9 screens in bacteria

2020 ◽  
Vol 48 (11) ◽  
pp. e64-e64 ◽  
Author(s):  
Alicia Calvo-Villamañán ◽  
Jérome Wong Ng ◽  
Rémi Planel ◽  
Hervé Ménager ◽  
Arthur Chen ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Cost Effective ◽  
Target Sequence ◽  
Guide Rna ◽  
E Coli ◽  
Genome Wide ◽  
High Throughput Screens ◽  
Target Activity ◽  
Target Effects

Abstract The ability to block gene expression in bacteria with the catalytically inactive mutant of Cas9, known as dCas9, is quickly becoming a standard methodology to probe gene function, perform high-throughput screens, and engineer cells for desired purposes. Yet, we still lack a good understanding of the design rules that determine on-target activity for dCas9. Taking advantage of high-throughput screening data, we fit a model to predict the ability of dCas9 to block the RNA polymerase based on the target sequence, and validate its performance on independently generated datasets. We further design a novel genome wide guide RNA library for E. coli MG1655, EcoWG1, using our model to choose guides with high activity while avoiding guides which might be toxic or have off-target effects. A screen performed using the EcoWG1 library during growth in rich medium improved upon previously published screens, demonstrating that very good performances can be attained using only a small number of well designed guides. Being able to design effective, smaller libraries will help make CRISPRi screens even easier to perform and more cost-effective. Our model and materials are available to the community through crispr.pasteur.fr and Addgene.

scholarly journals High-Throughput Silencing Using the CRISPR-Cas9 System

2015 ◽  
Vol 20 (8) ◽  
pp. 1027-1039 ◽  
Author(s):  
Mark Wade
Keyword(s):  
Functional Genomics ◽  
High Throughput ◽  
High Throughput Screening ◽  
Signaling Cascades ◽  
Gene Correction ◽  
Pooling Strategies ◽  
Rapid Generation ◽  
Interfering Rna ◽  
Multiple Signaling ◽  
Target Effects

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system has been seized upon with a fervor enjoyed previously by small interfering RNA (siRNA) and short hairpin RNA (shRNA) technologies and has enormous potential for high-throughput functional genomics studies. The decision to use this approach must be balanced with respect to adoption of existing platforms versus awaiting the development of more “mature” next-generation systems. Here, experience from siRNA and shRNA screening plays an important role, as issues such as targeting efficiency, pooling strategies, and off-target effects with those technologies are already framing debates in the CRISPR field. CRISPR/Cas can be exploited not only to knockout genes but also to up- or down-regulate gene transcription—in some cases in a multiplex fashion. This provides a powerful tool for studying the interaction among multiple signaling cascades in the same genetic background. Furthermore, the documented success of CRISPR/Cas-mediated gene correction (or the corollary, introduction of disease-specific mutations) provides proof of concept for the rapid generation of isogenic cell lines for high-throughput screening. In this review, the advantages and limitations of CRISPR/Cas are discussed and current and future applications are highlighted. It is envisaged that complementarities between CRISPR, siRNA, and shRNA will ensure that all three technologies remain critical to the success of future functional genomics projects.

High-throughput screening program for botanical extracts

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
L Hingorani ◽  
NP Seeram ◽  
B Ebersole
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Screening Program ◽  
Botanical Extracts

High throughput screening of microbial biodiversity for the discovery of novel cosmeceutical agents

Planta Medica ◽  
2015 ◽  
Vol 81 (16) ◽  
Author(s):  
K Georgousaki ◽  
N DePedro ◽  
AM Chinchilla ◽  
N Aliagiannis ◽  
F Vicente ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Microbial Biodiversity

High throughput screening to investigate Brazilian Cerrado biome plant extract bank chemical diversity

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
LS Espindola ◽  
RG Dusi ◽  
KR Gustafson ◽  
J McMahon ◽  
JA Beutler
Keyword(s):  
High Throughput ◽  
Plant Extract ◽  
High Throughput Screening ◽  
Chemical Diversity ◽  
Brazilian Cerrado ◽  
Cerrado Biome

High-throughput screening revealed a clinically relevant drug to induce sperm motility

2014 ◽  
Author(s):  
Clair Cochrane ◽  
Halil Ruso ◽  
Anthony Hope ◽  
Rosemary G Clarke ◽  
Christopher Barratt ◽  
...  
Keyword(s):  
Sperm Motility ◽  
High Throughput ◽  
High Throughput Screening
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