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Biopharmaceutical Assays & Screening glossary & taxonomy
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions? Mary Chitty
Last revised December 18, 2014


Related glossaries include  Drug Discovery & development  Drug safety   Drug Targets   Chemistry Combinatorial libraries & synthesis  Technologies:  Cell & tissue technologies   Labels, Signaling & Detection  MicroarraysMolecular Imaging  
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96, 384, 1536, 3456 well plates: See under microtiter/ microtitre plates 

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assay A set of operations having the object of determining the value of a quantity. In analytical chemistry, this term is synonymous with measurement. [IUPAC Compendium]

Generically a bioassay where biological activity is derived; associated with a bioactive effector molecule. Within the screening discipline, an assay will probably be robust enough and have the capacity to enable testing of up to 10,000 samples, generally with limited chemical diversity. [The precise definition of the following terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at Glaxo Wellcome.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery" Drug Discovery Today 5(7): July 2000] 

It could be argued that the rate-limiting factor in biology at the moment is not the speed of assays but devising the assays themselves; that is, establishing new and imaginative ways of measuring biological activity in vivo or in vitro and then using genetics or biochemistry to use the players - Kim Nasmyth ["Opinions on the potential of yeast biochemical genomics" in "The awesome power of yeast biochemical genomics" Trends in Genetics 16 (2): 49- 51 Feb. 2000  Narrower terms:  Enzyme- Linked Immunosorbent Assay ELISA, force assays, primary assays, secondary and tertiary assays; bioassay, cell assays, high content assays, homogeneous assays, immunoassay, quantitative assays, sandwich assay, single cell metabolism and enzyme assays, "smart" assays;  primary assays, secondary assays; Related terms: screening

assay development: The majority of assay development, the process of looking at the kinetics and pharmacology of an assay and ensuring it is properly arranged, has been done in the same manner for a number of years. But scientists are constantly looking for ways to tweak existing assays and develop new ones that are more precise and sensitive while being less expensive. ... [Boehringer Ingelheim scientist Carol Ann] Homon notes that, given the industry setting in which she works, when she talks about assay development she is thinking of automated assays. "One thing we have seen is taking the hand-performed assay and converting it over to an automation format. There's always some step in that assay that is difficult to convert for one reason or another. . . . As you go into the miniaturized formats, if you really want to maintain the quality of the assay, which is critical in our thinking. Assay Development Challenge, Drug Discovery & Development Sept 2007 

assay validation: Depending on how it's being used, assay validation can mean a number of different things, [Michael] Bleavins says. "You're really looking for an assay that does what you need it to do. What you would need in an assay if you're ranking early discovery compounds is nowhere near as extensive as what you would need if you were developing and validating an assay that affected a safety parameter that determined if you went to the next dose in a clinical trial."  Assay Validation Challenge, Drug Discovery & Development, Sept 2007   

Validation includes all the laboratory investigations that demonstrate that the performance characteristics of an assay are suitable and reliable for its intended analytical use. It describes in mathematical and quantifiable terms the performance characteristics of an assay. NIH Chemical Genomics Center Assay Guidance Glossary  See also  IUPAC Biomolecular Screening 

bead assays: Multiplex bead assays allow simultaneous analysis of multiple targets within one reaction, providing more information and higher sensitivity while using less sample than traditional ELISA assays. Drug discovery & Development Feb 2010 

binding assays: IUPAC Biomolecular Screening 

bioassay:  A procedure for determining the concentration or biological activity of a substance (e.g. vitamin, hormone, plant growth factor, antibiotic, enzyme) by measuring its effect on an organism or tissue compared with a standard preparation. IUPAC Medicinal Chemistry

A bioassay is a single step within a microarray experiment. There are 3 types of bioassays. A physical bioassay correspond to wet- lab microarray experimental step. A measured bioassay corresponds to a situation after feature extraction has been performed. A derived bioassay corresponds to data processing experimental steps. [MGED "bioassay"]  

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Bioassays for Biologics 
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biochemical assays: Measure how compounds bind to targeted molecules (such as receptors) or how compounds inhibit enzyme activities. CHA High- Content Analysis Market Outlook report, 2004

biological assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. MeSH 1999 Annotation assays using living-matter intermediate; check text: not all "bioassays" are MeSH term BIOLOGICAL ASSAY; Manual 22.27

biomolecular screening:  The term "biomolecular screening" became widely used in the late 1980's to broadly describe a new and rapidly adopted process for lead identification in drug discovery.  This new process involved screening natural product extracts and/or amassed compound collections, typically from pharmaceutical companies, in a random, unbiased manner to identify novel modulators of biological targets ... The screens encompassed bioassays that could be cell-based or purely biochemical in nature, and the need to screen increasing numbers of samples as time progressed, fostered the development of many new assay formats. IUPAC Biomolecular Screening glossary

cell assays, cellular assays: Cell biology is also looking less traditional these days. Companies ... have developed live cell assays that fully automate sample handling and quantify cellular characteristics such as motility, proliferation and morphology. The ability to track the behavior of individual cells over time permits data gathering on functional behavior not available in any other kind of assay. This functional assay technology is amenable to high throughput analysis, and therefore can occupy a niche complementary to many proteomic technologies focused on identification of potential therapeutic targets. 

Can be used for drug screening ... some companies are using such assays to gain insights about target function.... assays [can also be used] to get detailed functional information   Related term: Microarrays: phenotypic microarray Narrower term: live cell assays

cell-based assay: Assay in which the response of live cells to a test sample is measured.  Note 1: The type of cells, parameters measured, and detection systems used vary widely. 
Narrower term: high throughput cell based assays  Related terms: cell assays, cellular assays, cytotoxicity assay, chemotaxis assay, high-content screening assay.

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competitive binding assay:   IUPAC Biomolecular Screening Glossary

competitive immunoassays: Rely on the competition between a labeled and unlabeled antigen for a limited number of antibody binding sites. [B. Weigl et al “Novel Immunoassay formats for integrated microfluidic circuits” SPIE  BIOS 2000]

In a competitive immunoassay, the antigen in the unknown sample competes with labeled antigen to bind with antibodies. The amount of labeled antigen bound to the antibody site is then measured. In this method, the response will be inversely related to the concentration of antigen in the unknown. This is because the greater the response, the less antigen in the unknown was available to compete with the labeled antigen. Wikipedia  accessed Feb 25 2011  Broader term: immunoassay; Related term: competitive PCR

compound validation: A process to quickly determine whether a molecule identified in a screen or assay will eventually lead to a drug. If you look at the costs of developing compounds into drugs, the most costly failures result from toxicity or pharmacokinetic liabilities rather than from their failure to act on the target.  Related terms: Drug Targets

Conformation-Dependent Immunoassays CDI: A technique for detecting prions in tissue, developed in recent years by UCSF scientists, is significantly more sensitive than the diagnostic procedures currently used to detect the lethal particles in samples of brain tissue from patients, according to a study performed by a UCSF team.  Diagnosis of prions in patients should utilize novel strategy, conformation-dependent immunoassay  Medical News 22. February 2005 05:36 

counterscreens:  Counterscreens define the action of a potential compound on a particular class of drug targets. These assays usually include drug targets of the same family like the kinases. Logically, counterscreens also help to confirm mechanism of action and selectivity of the drug. Selectivity often increases as potency increases.  MP Biomedicals LLC Counterscreens and Selectivity See definition in  IUPAC Biomolecular Screening Glossary

derived bioassay: See under bioassay
dissociator assays: Proteomics

diversity screening: The drivers behind the current ethos of large- scale diversity HTS are rooted in the desire to build an improved hit identification process, and are based on the simple model of testing everything. The key activity over the past five or so years has been scaling: taking the existing model and increasing capacity by application of technology. [Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5 (7) : July 2000] 

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druggable genome: Drug discovery & development 
end-point assay: See definition in  IUPAC Biomolecular Screening Glossary

enzyme assays: Methods used to measure the relative activity of a specific enzyme or its concentration in solution. Typically an enzyme substrate is added to a buffer solution containing enzyme and the rate of conversion of substrate to product is measured under controlled conditions. Many classical enzymatic assay methods involve the use of synthetic colorimetric substrates and measuring the reaction rates using a spectrophotometer. MeSH 2010

Enzyme-Linked Immunosorbent Assay ELISA: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme- antibody- antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [MeSH, 1986]  See also definition in  IUPAC Biomolecular Screening Glossary

enzyme linked immunospot assay: A method of detection of the number of cells in a sample secreting a specific molecule. With this method a population of cells are plated over top of the immunosorbent substrate that captures the secreted molecules. MeSH 2011

equilibrium assay: See definition in  IUPAC Biomolecular Screening Glossary

focussed screening: Focussed screening is now well established as a successful hit generation strategy. With focussed screening, it should also be possible to use an assay that is more appropriate, rather than one that works well at a large scale.  [Martin J. Valler,  Darren Green  "diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5 (7): July 2000] 

fragment based drug discovery: Fragment-based approaches to lead discovery are rapidly gaining interest in many labs as they have established themselves as a useful and efficient way to explore new leads for drug candidates. Several technologies have matured into reliable methods to detect binding of fragments, to screen for new targets and to optimize leads. Includes how to select the most suitable projects; how  and when to use screening methods such as crystallography, NMR or mass spec, either as a standalone technique or complimentary; and how to correctly predict binding. Fragment-Based Drug Discovery  April 2012  Table of Contents | Tables and Figures  

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Comparison of development candidates derived from fragment-based screens has suggested that such an approach can provide compounds with more drug-like properties than those derived from more conventional screening efforts.

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functional bioassays:  Here, the concept of an array of 'functional' bioassays is presented which has ultimately been developed from the classical tool of mode of action diagnosis by symptoms. These bioassays are designed to differentiate between the distinct responses of the multiple organization units (plant, tissue, meristematic cell, organelle), developmental stages, types of metabolism (phototrophic, heterotrophic) and physiological processes in the plant organism. The response pattern to a herbicide can be viewed as the end result of changes induced in the molecular and biochemical process chain and should be diagnostic of its physiological mode of action.  K. Grossmann, What it takes to get a herbicide's mode of action. Physionomics, a classical approach in a new complexion, Pest Manag Sci.  Jan 20, 2005   Related term: physionomics 

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See also RNAi screening
Genome Editing for Functional Genomics Screens - Part B

heterogeneous assay: One or more assay components are present in solid phase at time detection. (e.g.: SPA, cells or IMAP). NIH Chemical Genomics Center Assay Guidance Glossary

high content analysis: Applications, technology and market aspects of high-content analysis (HCA)—a field that originated when automated microscopic imaging technology joined with the high-throughput screening paradigm that signified the birth of “industrialized drug discovery.” High-Content Analysis Report  December 2011 Table of Contents | Tables and Figures 
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See also live cell imaging 

Many processes can be studied using HCA, including intracellular translocation of proteins; movement of proteins in response to activation of a receptor or a cellular pathway; and protein co-localization. Such studies have enormous potential to streamline drug discovery.  Jim Kling, High Content Analysis BioIT World 6 (9): 26- 30 Nov 2007 

High content analysis (HCA) is the convergence between cell-based assays, high-resolution fluorescence imaging, automation and advanced image processing and analysis software. It has been widely adopted in the pharmaceutical and biotech industries for target identification and validation and as secondary screens to reveal potential toxicities or to elucidate a drug’s mechanism of action. In particular, HCA has made inroads into R&D applications where high throughput screening (HTS) has proven inadequate, such as measuring multiple biological pathways simultaneously, or revealing off-target drug effects. HCA has stepped into this void by demonstrating how particular proteins are affected by the application of a molecule to the cell line of interest.   Related/equivalent terms: high content assays,  high content screening, high content cellular analysis

high-content screening HCS: The area of High Content Screening is moving at a very rapid pace. It is hard to keep up. The purpose of this website is to provide a forum for those working in this field, a mechanism for exchange of information, an opportunity to develop educational tools and a facility to create training opportunities. Purdue Univ. Cytometry Laboratories    Related term:  high content analysis

High Throughput Screening HTS:   Greater than 100,000 compounds screened per screen NIH Chemical Genomics Center Assay Guidance Glossary

Process for rapid assessment of the activity of samples from a combinatorial library or other compound collection, often by running parallel assays in plates of 96 or more wells. IUPAC Combinatorial Chemistry

Currently, researchers must systematically screen tens or hundreds of thousands of small molecules to find a successful match between a chemical and its target. This process is known as high-throughput screening or HTS. The capacity for HTS has been built within the pharmaceutical and biotechnology sectors for the purposes of drug development over the last ten years, but similar resources have not existed in the public sector. NIH Common Fund, Molecular Libraries

Traditionally describes the running of a large-scale assay campaign looking at the effects of a large number of compounds on a biological target.   Broader term: screening   Narrower term: ultra high throughput screening Related terms: high content analysis, high content screening, throughput

high throughput screening assays: Rapid methods of measuring the effects of an agent in a biological or chemical assay. The assay usually involves some form of automation or a way to conduct multiple assays at the same time using sample arrays. MeSH 2010

hit:  Library component whose activity exceeds a predefined, statistically relevant threshold. IUPAC Combinatorial Chemistry

A molecule with robust dose­ response activity in a primary screen and known, confirmed structure. The output of most screening. [The precise definition of the following terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at Glaxo Wellcome.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery" Drug Discovery Today 5(7): July 2000]   
Related terms: High Throughput Screening HTS, hit optimization library, lead discovery, screening. Narrower term: integrated hit identification, progressible hit

hit to lead: Reaching the next rung in hit-to-lead and lead optimization poses persistent challenges in the quest for successful drugs. As costs escalate, innovative approaches are needed to develop more efficient processes that lead to optimized compounds. With the help of emerging technologies – software, modeling, automation – Hit to Lead to Optimization can progress into a new age of drug discovery.   Related term: lead optimization

homogeneous assay: All assay components exist in solution phase at the time of detection (e.g. none of the components are in beads or cells). Technically no component scatters light.  NIH Chemical Genomics Center Assay Guidance Glossary

Any assay method in which all the components of the assay are present during measurement. The reactions occur in solution generally without a solid-phase attachment. 

image analysis/image processing: In the context of high- content screening, these efforts involve drawing conclusions from image- based data, typically from living cells that have been exposed to compounds of interest. Analyzing such images can be challenging for many reasons, including the transient nature of cellular events and the fact that image- processing algorithms are still not robust enough for certain important applications (e.g., pattern recognition).  Related terms: Molecular Imaging

immunoassay: A ligand- binding assay that uses a specific antigen or antibody, capable of binding to the analyte, to identify and quantify substances. The antibody can be linked to a radiosotope (radioimmunoassay, RIA), or to an enzyme which catalyses an easily monitored reaction (enzyme- linked immunosorbent assay, ELISA), or to a highly fluorescent compound by which the location of an antigen can be visualized (immunofluorescence). [IUPAC Compendium] 

An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods. Such assays are based on the unique ability of an antibody to bind with high specificity to one or a very limited group of molecules. Wikipedia  accessed Feb 25 2011   Narrower term: competitive immunoassay Related term: ELISA

immunometric assay: See  sandwich assay

in vitro adventitious assay: Biologically based drugs need to be tested to ensure that they are free from contaminating viruses; one test is an assay known as the in vitro adventitious assay. However, certain viral cancer therapies are very difficult to test because the product itself kills the cells that are used in the test, resulting in delays in early-phase product development. In 2007, FDA scientists began developing ways to neutralize this problem, thereby enhancing the ability to test these products for safety while reducing the need for sponsors to invest time and money in test method R&D.   FDA's Critical path opportunities: Harnessing Bioinformatics, 2007 

Adventitious means of external origin, or not normally expected or found. 

kinetic assay: See definition in  IUPAC Biomolecular Screening Glossary

lead: A representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development programme.  [The precise definition of the following terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at Glaxo Wellcome.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000] Related term: hit

lead discovery: The process of identifying active new chemical entities, which by subsequent modification may be transformed into a clinically useful drug. [IUPAC Medicinal Chemistry] 
Related terms: drug discovery, hit, lead generation, lead discovery library, lead optimization, screen 

lead generation: Strategies developed to identify compounds which possess a desired but non- optimized biological activity. [IUPAC Medicinal Chemistry]  Related terms: drug development, hit, lead discovery, lead optimization

lead hopping:   Tripos  Related terms:  Chemistry  scaffold hopping  Drug targets  target hopping

lead identification: Once the therapeutic target has been identified, scientists must then find one or more leads (e.g., chemical compounds or molecules) that interact with the therapeutic target so as to induce the desired therapeutic effect.  Lifesciences Montreal, Discovery of a New Drug 

lead-like: Intrinsically, lead-likeness and drug-likeness are the descriptors of potency and selectivity, but also absorption, distribution, metabolism, toxicity, and scalability. Until now, these parameters were optimized sequentially, but nowadays it is believed that these parameters should be optimized simultaneously. Thierry Langer, G Wolber, Virtual combinatorial chemistry and in silico screening, Pure and Applied Chemistry 76 (5): 991– 996 , 2004 

lead optimization: Drug-induced adverse events account for most drug recalls and delays experienced in gaining regulatory approvals. While improvements in pre-clinical screening and clinical trial design have helped with better detection and monitoring of such adverse events, the problem still persists and often goes unnoticed until the compound is further along in development and testing.   

The synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness. [IUPAC Medicinal Chemistry] Related terms: hit to lead,  drug development;  Pharmacogenomics ADME, toxicogenomics; Drug discovery & development prototype  Narrower term: parallel optimization

lead prioritization: One of the major steps in lead prioritization is an assessment of compound binding to plasma proteins, because it affects both the pharmacokinetics and pharmacodynamics of the compound in vivo.  Development of a high throughput equilibrium dialysis method , Ilona Kariv, Hong Cao, Kevin R. Oldenburg, J. Pharm. Sci. 90( 5) : 580- 587, 200 DOI: 10.1002/1520-6017(200105)90:5<580::AID-JPS1014>3.0.CO%3B2-4   AAPS Pharmaceutica 

lead validation: With no shortage of drug targets, increasing emphasis is being placed on lead validation. One key challenge is developing high throughput screensRelated term: target validation.

ligand binding assays: One of the key reasons Protein Therapeutics have achieved significant success stems from their ability to bind to specific targets, such as receptors or cell surface proteins, with high affinity. As Protein and other Macromolecule Therapeutics become more complex, bioanalytical challenges have increased, especially for multi-domain and multi-valent biopharmaceuticals.  Ligand Binding Assays (LBAs), which indirectly measure reactions with the binding reagents, continue to be the preferred method of analyzing macromolecule therapeutics.  However, to date no clear guidance or consensus exists that outlines how to consistently monitor and validate specificity and selectivity for ligand binding assays, and what methods are necessary to differentiate between “free” and “total” therapeutic.  Additionally, there is a need to establish criteria for reagent quality, lot-to-lot consistency, and maintaining a sustainable reagent supply.  

live cell assays:  Can be used to obtain functional information on a wide variety of cellular effects, including apoptosis, proliferation, differentiation, migration and protein secretion. Enables a better understanding of protein functionality in normal and diseased states. 

massively parallel: Many (assays or other procedures) at once.  Related term: Gene amplification & PCR multiplexing

measured bioassay: See under bioassay

microplate reader: Created from the tube spectrophotometer designs of the 1970s to save precious antibody samples. At first clumsy and inaccurate, absorbance microplate readers have evolved to pack unbelievable power and precision, replacing cuvette spectrophotometers for most multisample applications.1 Continuous improvement is enhancing the classic designs to embrace the world of high- throughput (HT) screening and to allow complete analytical automation.2 To handle the HT range (more than 10 microplates a day or 1,000 assays), many instruments now allow robotic handling of plates "stacked" in accessory plate handlers.  Jorge D. Cortese " Well Read: Technological improvements are pushing microplate readers into the 21st century's high-speed, computerized world" Scientist 14 (19): 24, Oct. 2, 2000

microtiter plate, microtitre plate: Sample holding device used in combinatorial chemistry and high throughput screening for cloning of PCR products and construction of cDNA libraries in expression vectors. Comes in 96, 384, 1536 and 3456- well formats. Related term: sample

multiplex assays:  Assay technologies have been evolving since scientists first discovered they could measure glucose, insulin, and several hormones in the blood to help them diagnose disease. Early instruments such as the Ames Reflectance Meter, used for detecting glucose levels, have morphed into such sophisticated systems as flow cytometers. The Human Genome Project provided the basics for researchers to launch into the field of human genomics and they needed the tools to accomplish this. DNA microarrays allowed for massively parallel gene expression analyses. Scientists soon discovered that while the genomewide assays were extremely valuable, there were genes of interest that they had difficulty measuring when they got hundreds of data points from a microarray. Low- to mid-density assays have allowed scientists to pinpoint the genetic code for a variety of uses, from genetic heredity studies to drug metabolism and patient stratification. Insight Pharma Reports, Multiplex assays in Translational Medicine: Technologies, Applications, and Future Directions, 2008 

Multiplex assays for simultaneously detecting several biomarkers in a single sample, traditionally used in discovery proteomics, are becoming popular in clinical diagnostics research. The range of clinical applications for these assays is broad and includes autoimmune disease, infectious disease, oncology, cardiology, and endocrinology testing, as well as metabolomics and toxicology screening. The anticipated advantage of multiplex assays in clinical diagnostics is the fact that a panel of several biomarkers has better diagnostic value than a single analyte. However, some substantial obstacles are in the way of clinical utility of identified sets of biomarkers. In its inaugural year, this conference will present solutions and case studies for an array of topics related to clinical laboratory implementation of non-genomic multiplex assays such as regulatory challenges, commercialization issues, and technological barriers and advances. A comprehensive account of the clinical proteomics and metabolomics technologies will be introduced throughout the conference including bead-based immunoassay platforms, mass spectrometry-based multiplexed protein assay platforms, custom microplates, nanotechnology solutions, etc. Special emphasis will be placed on the regulatory issues related to the approval process of multiplex platforms and assays. Translating Proteomics & Metabolomics into the Clinical Laboratory  August 23-24, 2011 Washington DC  

Narrower term: multiplex DNA hybridization arrays: Microarrays categories 

multiwell plate: See microtiter plate, microtitre plate.

non competitive immunoassays: In noncompetitive immunoassays, also referred to as the "sandwich assay," antigen in the unknown is bound to the antibody site, then labeled antibody is bound to the antigen. The amount of labeled antibody on the site is then measured. Unlike the competitive method, the results of the noncompetitive method will be directly proportional to the concentration of the antigen. This is because labeled antibody will not bind if the antigen is not present in the unknown sample. Wikipedia  accessed Feb 25 2011  Broader term: immunoassay

phenotypic assays: [phenotypic approaches (function-first, reverse chemical biology)] have the advantage of identifying drug leads and clinical candidates that are more likely to possess therapeutically relevant [molecular mechanisms of action] MMOAs. Phenotypic screening in cancer drug discovery — past, present and future John G. Moffat,  Joachim Rudolph & David Bailey Nature Reviews Drug Discovery 13, 588–602 (2014) doi:10.1038/nrd4366 Published online 18 July 2014

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Phenotypic Screening
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phenotypic screens: look at the effects, or phenotypes, that compounds induce in cells, tissues or whole organisms … Beginning in the 1980s, advances in molecular biology and genomics led to phenotypic screens largely being replaced by screens against defined targets implicated in disease. … some researchers have concluded that reductionist approaches such as target-based screening are useful but may also limit the breadth of new findings. Phenotypic screening, take two Kotz, J.SciBX 5(15); doi:10.1038/scibx.2012.380 Published online April 12 2012

The systematic classification and characterization of phenotypes is essential for ultimately mapping the genes responsible for normal and abnormal development and physiology. In any search for mutations or altered functional expression, identification depends on phenotypic screening and its ability to detect variation from normal. The challenge is to develop efficient, systematic and comprehensive phenotypic screening procedures and tools that will permit comparison between laboratories, temporally, and between different strains of mice. This is a necessary step before utilizing chemical or other mutagenesis methods to produce large numbers of mutant mice for the investigation of normal and abnormal development and physiology. ... a primary focus of this program is the development of high throughput phenotyping assays or tests that could efficiently, rapidly, and systematically be used to screen anywhere from 5,000 to 20,000 mice per year for alterations in cardiovascular, pulmonary, hematologic or sleep physiology. This could include, but not be limited to, biochemical surrogate markers, noninvasive imaging modalities, microarray analysis, or indicator screens. Another goal is to develop new phenotyping techniques or methods for heart, lung, blood, and sleep disorders that would accelerate the emergence of new concepts and improve our understanding of structural, metabolic, and functional relationships in cardiopulmonary, and blood systems.  Development of mouse phenotypic screens for heart, lung, and blood diseases, National Heart, Lung and Blood Institute, NIH, US, Apr. 13, 1999, Request for Application

Compare targeted based drug discovery, screens

primary assay: Assays of drugs done on a single drug  target or small groups of targets 

primary screening:   Primary screening, which is higher throughput than secondary screening, typically seeks to identify which compounds bind to targets of interest, to what degree of affinity. In primary screens researchers may seek to determine what compounds bind to and inhibit targets of interest. 

progressible hit: A representative of a compound series with activity via an acceptable mechanism of action and some limited structure­ activity relationship. The precise definition of the following terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at Glaxo Wellcome.  Martin J. Valler,  Darren Green  Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000]  Related term: Combinatorial libraries & synthesis  chemistry space

random screening: A staple of the pharmaceutical industry for many years. Now largely replaced by varying combination of combinatorial chemistry and/or rational drug design.  Related terms: diversity screening, focussed screening Broader terms: screen, screening

RNAi screening: RNA interference (RNAi) is being commonly used as a screening tool for identifying and validating potential drug targets, exploring cellular pathways, and for whole-genome screening studies. The screens developed, using both small interfering RNA (siRNA) and short hairpin (shRNA), are now fairly robust and sensitive and can be performed in a reliable and high-throughput fashion.    

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sandwich assay:  The most powerful ELISA assay format is the sandwich assay. This type of capture assay is called a “sandwich” assay because the analyte to be measured is bound between two primary antibodies – the capture antibody and the detection antibody. The sandwich format is used because it is sensitive and robust. Thermo Scientific Overview of ELISA 

screen: An optimized, streamlined assay format with characterized robustness to diverse chemical types and conditions such that testing of 10,000 samples is both feasible and cost effective. The spectrum of low- throughput screening (10,000­ 50,000 assay points) medium- throughput screening (50,000­100,000 data points) and high- throughput screening (100,000­ 500,000 data points) can be defined. The scale of implementation of a given screen is greatly influenced by format, application of technology (e.g. automation), time and resource constraints. [The precise definition of the[se] terms varies widely between drug discovery companies. The meanings given here are aligned with the use of the terms within the lead discovery function at GlaxoWellcome.  Martin J. Valler,  Darren Green  "Diversity screening versus focussed screening in drug discovery " Drug Discovery Today 5(7): July 2000] 

screening: Pharmacological or toxicological screening consists of a specified set of procedures to which a series of  compounds is subjected to characterize pharmacological and toxicological properties and to establish dose- effect and dose- response relationships. [IUPAC Tox]

The use of in vitro biochemical assays, or tests, to detect compounds which modulate the activity of a target (i.e., enzyme inhibitors, receptor agonists or antagonists). [Oxford Molecular]  

While drug screening is often talked about in the context of achieving hits, it is useful to note that the Oxford English Dictionary definition of screening specifies that this is "esp. for the detection of unwanted attributes or objects".  Narrower terms: diversity screening, focussed screening, HTS High Throughput Screening, synthetic lethal screening, Ultra High Throughput Screening UHTS; Drug targets target screening  Not the same as screening in Molecular Medicine Related terms: assay, I.R. Thermography 

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secondary assays (and tertiary assays): Undertaken after primary screening has identified "hit" compounds against drug  targets, are more complicated - and time-consuming - tests of a drug and include ADME/Tox (absorption, distribution, metabolism, excretion/toxicology) studies (e.g., done on mice or rats). Test a drug against more than one target, complicated and time- consuming, so they have not been considered practical for use in very early drug development.... . The secondary and tertiary assays tell you more biology. ...Typically, secondary and tertiary assays are more comprehensive, but they also take longer, and they are more complex and less reproducible. 

secondary screening:  Secondary screening, which is lower throughput than primary screening, seeks to provide more detailed information about compounds than just their binding affinity. For example, secondary screens may shed light on mechanism of action and other parameters. 

As the primary screening technologies are becoming increasingly automated and high-throughput, the drug discovery bottleneck is shifting downstream towards secondary screening and lead optimization. This is the area where researchers had the most experience with High Content Screening. The high-content cellular information on lead specificity, bioavailability, and ADME/Tox allows researchers to prioritize leads with more confidence and impact the bottom line by reducing late- stage attrition.

small molecule screening:  The basic goal of small- molecule screening is the identification of chemically 'interesting' starting points for elaboration towards a drug. A number of innovative approaches for pursuing this goal have evolved, and the right approach is dictated by the target class being pursued and the capabilities of the organization involved. A recent trend in high- throughput screening has been to place less emphasis on the number of data points that can be produced, and to focus instead on the quality of the data obtained.  Walters WP, Namchuk M., Designing screens: how to make your hits a hit. Nature Reviews Drug Discovery 2003 Apr;2(4): 259- 266 

"smart" assays: May be operationally defined as a screening system that by its very operation conveys information about new chemistry or biology of "hits" in the system. For example, assays of interest to promote may couple the use of a cloned and expressed target protein or a nucleic acid sequence in tandem with a chemical or biosynthetic process that generates molecules for further study. Alternatively, the use of genetically definable yet underexplored organisms such as yeast, Drosophila, or C. elegans, production of expression vectors that may operate only in the presence of a compound with the desired properties, development of detection techniques based on novel patterns of molecular recognition, or strategies that require the operation of a particular molecular target to be a basis for detection would all examples. [NCI, CANCER DRUG DISCOVERY: DIVERSITY GENERATION AND SMART ASSAYS, RFA: CA-97-006, May 9, 1997]  

target-based drug discovery: [target-first, forward chemical biology]  is not an intrinsically inferior approach but … is more likely to fail if target modulation is prioritized at the expense of understanding the most desirable MMOAs. These mechanisms can best be demonstrated by functional and phenotypic assays. Phenotypic screening in cancer drug discovery — past, present and future John G. Moffat,  Joachim Rudolph & David Bailey Nature Reviews Drug Discovery 13, 588–602 (2014) doi:10.1038/nrd4366 Published online 18 July 2014

target-based screens. measure the effect of compounds on a purified target protein via in vitro assays. … Over the last decade, however, some drug developers have questioned whether an over-reliance on genetic approaches to validating targets for subsequent target-based drug discovery has resulted in reduced success in discovering first-in-class medicines. Phenotypic screening, take two Kotz, J. SciBX 5(15); doi:10.1038/scibx.2012.380 Published online April 12 2012 

Compare targeted based assays, screens

tertiary assays: See secondary assays (and tertiary assays)

throughput: Output or production, rate at which something can be processed.  

Ultra High Throughput Screening (uHTS) : A screening rate of  100,000 assays per day. [IUPAC Combinatorial Chemistry] 
Greater than 500,000 compounds screened per screen. NIH Chemical Genomics Center Assay Guidance Glossary

Narrower term: cell- based uHTS; Broader term: High Throughput Screening HTS 

virtual screening: Selection of compounds by evaluating their desirability in a computational model. Also termed in silico screening. IUPAC Combinatorial Chemistry

The Computational Chemistry and Biology group is developing in silico molecular models in order to understand in microscopic detail how proteins interact with small molecules such as drugs. The aim is to create global-level models of gene interaction networks derived from bioinformatics analyses of large-scale micro-array experiments and biological databases. A variety of computational tools ranging from physics-based detailed molecular simulations to pattern-recognition and data-mining approaches in bioinformatics are utilized. Genomic database mining and gene-network analysis, together with the development of web-based software for DNA micro-array primer design, database management, processing, analysis and visualization, are some of the competitive capabilities of the bioinformatics group. Enabling Technologies Program, National Research Council Canada 2005 
Wikipedia   Narrower terms: grid based virtual screening, high throughput virtual screening  Related terms: docking; Pharmaceutical biology & chemistry ligands, receptors; Combinatorial libraries & synthesis 

MeSH Medical Subject Headings, PubMed 
Assay Guidance Manual, NCBI 
Bioassay Ontology
IUPAC Glossary of terms in Biomolecular Screening 2011

High Content Analysis, Technologies, Applications, Market Analysis,  Insight Pharma Reports, 2007

Multiplex Assays in Translational Medicine: Technologies, Applications, and Future Directions, 2008  

Alpha glossary index
How to look for other unfamiliar  terms

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.

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