|
Chemistry
term index Drug
discovery term index Informatics
term index Technologies
term index Biology
term index Finding guide to terms in these glossaries Site
Map Related glossaries include Drug
Discovery & development Drug safety
Drug Targets Chemistry Combinatorial libraries &
synthesis Technologies: Cell & tissue
technologies Labels, Signaling
& Detection Microarrays, Molecular
Imaging
96, 384, 1536, 3456
well plates: See under microtiter/ microtitre plates
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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf 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 http://www.dddmag.com/articles/2007/09/assay-development-challenge
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 http://www.dddmag.com/articles/2007/09/assay-validation-challenge
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 http://assay.nih.gov/assay/index.php/Section18:Glossary
See
also IUPAC
Provisional glossary 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 http://www.dddmag.com/article-Washing-Methods-for-Multiplex-Bead-Assay-Platforms-2110.aspx
binding assays: See IUPAC
Provisional glossary Biomolecular Screening
bioassay:
Bioassays for Biologics March 21-22, 2012 • Baltimore, MD Program | Register | Download
Brochure
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"] http://www.mged.org/Workgroups/MAGE/bioassay.html
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:
Over the past 15 years, high throughput screening (HTS) of
small molecules has become a mainstay in the drug discovery process both in lead
discovery and lead optimization. In both HTS and routine screening to optimize
lead structures, new technologies, techniques and terminology have emerged. May
2009 - A manuscript is being prepared for publication in Pure
Appl. Chem. A final document is submitted to public review comments until
30 September 2009. > see Glossary of Terms used in Biomolecular Screening,
IUPAC Recommendations 2008 provisional
recommendations about 150 terms defined.
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
Google = "cell assays" about 1,900
Aug. 21, 2002; about 106,000 Nov 13, 2009
cellular assays" about 1,130 Aug. 21, 2002; about 55,300 Nov 13, 2009
Related term: Microarrays:
phenotypic microarray
Narrower term: live cell assays
cell-based
screening:
Novel Technologies for Cell Based
Screening June 8-9, 2011 • Philadelphia, PA Program
| Register
| Download Brochure
See IUPAC
Provisional glossary Biomolecular Screening Google = about 2, 780 Aug. 21, 2002;
about 9,780 Mar. 22, 2004; about 202,000 Nov 13, 2009 Narrower term: high throughput cell based
assays Related terms: cell assays, cellular assays
cellular screens: See cell
based screening Google = about 51 Aug. 21, 2002;
about 554 Nov 10, 2006
competitive
binding assay: IUPAC
Provisional glossary Biomolecular Screening
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] http://www.micronics.net/spiebios2000/spie2000novelIAformats.htm
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 http://en.wikipedia.org/wiki/Immunoassay
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 http://www.news-medical.net/news/2005/02/22/7870.aspx
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 http://www.mpbio.com/index.php?cPath=2_2010_2053_2143&open=applications&country=223
See definition in IUPAC
Provisional glossary Biomolecular Screening
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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
druggable
genome: Drug discovery
& development
end-point
assay: See definition in IUPAC
Provisional glossary Biomolecular Screening
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
Provisional glossary Biomolecular Screening
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
Provisional glossary Biomolecular Screening
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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
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
Fragment-Based Drug Discovery
April
17-18, 2012 • San Diego, CA Program | Register | Download
Brochure
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.
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
functional genomics
screening: Covers the latest in the use of chemical genomics tools, cDNA
overexpression assays and the potential use of micro RNA (miRNA) and long
non-coding RNAs for identifying and validating drug targets, exploring unknown
cellular pathways, and for performing translational studies such as, biomarker
discovery, and drug modifier screens. Functional
Genomics Screening Strategies October 2-3, 2012 • Boston, MA Program | Register | Download Brochure  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 High-Content Analysis 2013 meeting
will focus on the next steps of technology development, including new assays and
probes, more advanced image analysis and data management, and novel biological
models for screening. We will also cover case studies and applications in
compound screening, cytotoxicity evaluation, stem cell research, and functional
analysis High-Content
Analysis January 8-11, 2013 • San Francisco, CA Program | Register | Download Brochure
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
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 http://www.bio-itworld.com/issues/2007/nov/cover-story-high-content-analysis/
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. Google =
about 420 July 14, 2004, about 9,860 Aug. 22, 2005; about 42,000 May 15, 2006;
about 75,100 Nov 10, 2006; about 65,100 Apr 6, 2007, about 31,700 Sept 10, 2007;
about 299,100 Nov 13, 2009 Related/equivalent
terms: high content assays, high content screening high content
assays: Google = about 164
July 14, 2004, about 381 Aug. 22, 2005; about 654 Nov 10, 2006, about 784 Sept
10, 2007; about 93,100 Nov 13, 2009 High content
cellular analysis:
Google = about 122
Aug. 6, 2004, about 192 Aug. 22, 2005; about 329 Nov 10, 2006, ab out 1,090 Sept
10, 2007
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 http://www.cyto.purdue.edu/HCS/
Google = about 4,100
July 14, 2004, about 15,800 Aug. 22, 2005; about 124,000 Nov 10, 2006; about
239,000 Sept 10, 2007; about 89,100 Nov 13, 2009 Related
term: high content analysis
High Throughput Screening HTS:
Greater than 100,000 compounds screened per screen
NIH Chemical Genomics Center
Assay Guidance Glossary
High-throughput
screening technologies are constantly evolving: new assay formats and
instrumentation are being developed each day.
Tools & Technology for HTS High Throughput Screening June
7-8, 2011 • Philadelphia, PA Program
| Register
| Download Brochure 
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] Traditionally describes
the running of a large-scale assay campaign looking at the effects of a large
number of compounds on a biological target. Google = about 260,000
Aug. 22, 2005; about 1, 050, 000 Nov 10, 2006 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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
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. http://www.fluidigm.jp/gloss/gloss_homogeneous.htm
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 http://en.wikipedia.org/wiki/Immunoassay
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 http://www.fda.gov/oc/initiatives/criticalpath/report2007.html#topic3 Adventitious
means of external origin, or not normally expected or found.
kinetic assay:
See definition in IUPAC
Provisional glossary Biomolecular Screening
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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
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 http://www.iptonline.com/articles/public/IPTFIVE46NP.pdf
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 http://www.montrealinternational.com/sciences/drug/discovery-lead-id.html
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 http://www.iupac.org/publications/pac/2004/pdf/7605x0991.pdf
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.
Early
ADME and DMPK Predictions for Better Lead Optimization June 8-9,
2011 • Philadelphia, PA Program | Register | Download Brochure
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 http://www.aapspharmaceutica.com/search/view.asp?ID=4798
lead validation:
With no shortage of drug targets, increasing emphasis is being placed
on lead validation. One key challenge is developing high throughput screens. Related 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] http://www.the-scientist.com/yr2000/oct/profile_001002.html
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: 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
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
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 http://en.wikipedia.org/wiki/Immunoassay
accessed Feb 25 2011 Broader term: immunoassay
phenotypic screening:
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 http://grants1.nih.gov/grants/guide/rfa-files/RFA-HL-99-010.html
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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
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. RNAi for Functional Screening November
3-4, 2011 • Boston, MA Program | Register | Download Brochure
Best Practices for Setting Up Effective RNAi Screens DVD November 3, 2010 •
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 http://www.piercenet.com/proteomics/browse.cfm?fldid=f88adec9-1b43-4585-922e-836fe09d8403 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] http://www2.uah.es/farmamol/Public/PDF_files/screening.pdf
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
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] http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-97-006.html
synthetic lethal screening:
Functional
genomics
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
Google = about 6,250
Aug. 22, 2005; about 32,500 Nov 10, 2006 uHTS about 35,400 Nov 10, 2006
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 http://www.nrc-cnrc.gc.ca/eng/programs/bri/enabling.html
Wikipedia http://en.wikipedia.org/wiki/Virtual_screening
Google = about 9,480
Mar. 1, 2004, about 55,000 March 11, 2005, about 148,000 Aug 12, 2008 Narrower terms: grid
based virtual screening, high throughput virtual screening Related terms: docking; Pharmaceutical
biology & chemistry ligands, receptors;
Combinatorial libraries &
synthesis
Bibliography
MeSH Medical Subject Headings, PubMed http://www.ncbi.nlm.nih.gov/mesh
NIH Chemical Genomics Center Assay Guidance Glossary
http://assay.nih.gov/assay/index.php/Section18:Glossary
100 plus definitions.
IUPAC is
working on a Glossary of terms in Biomolecular Screening http://www.iupac.org/projects/2004/2004-019-3-700.html
Number: 2004-019-3-700
High
Content Analysis, Technologies, Applications, Market Analysis, Insight
Pharma Reports, 2007
Multiplex Assays in Translational Medicine:
Technologies, Applications, and Future Directions, 2008 http://www.insightpharmareports.com/Reports_report.aspx?id=71444&r=555
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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