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targets & disease targets glossary & taxonomy
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targets & disease targets glossary & taxonomy
The
true test of validation comes only when a selective inhibitor for the chosen
target is advanced to the clinic and shown to be efficacious in the appropriate
human disease. However, advancing the wrong target to this stage is a costly
mistake. Much of the impact of genomics on drug development thus far has
been focused on the identification and validation of biological targets. While
much of this research on targets is based only on comparisons of the biology of
health and disease, sooner or later it becomes critical to integrate the
activity of chemical compounds with the body. Drug
discovery term index: Guide to terms in these
glossaries
Site Map Related glossaries include: Applications Drug
discovery & development Molecular
Diagnostics allosteric
modulators: Allosteric modulation of GPCRs is rapidly emerging as a major
area of interest for pharmaceutical discovery because allosteric modulators have
the potential to show dramatically improved safety, tolerance, and side-effect
profiles compared to traditional orthosteric agonists and antagonists. Allosteric
Modulators October 2-3, 2012 • Boston,
MA Program | Register | Download Brochure
binding site:
A specific region (or atom) in a molecular entity
that is capable of entering into a stabilizing interaction with another
molecular entity. IUPAC Bioinorganic
The reactive parts of a macromolecule that directly participate in its
specific combination with another molecule. MeSH, 1968
Related terms: ligand; receptor
mapping.
Narrower term: binding sites, antibody
binding sites, antibody:
Local surface sites on antibodies which react with antigen determinant sites on antigens. They are formed from parts of the variable regions of the Fab fragment of the immunoglobulin.
MeSH, 1973
biological
target A biological target is a
biopolymer such as a protein or nucleic acid whose activity can be modified by
an external stimulus. accessed Jan 10, 2011 en.wikipedia.org/wiki/Drug_target cancer
cell metabolism: The fact that cancer cells have an altered glucose
metabolism has sparked new interest in the pharmaceutical industry. Reversing
the increased glucose consumption in cancer cells is an important step and has
great potential for therapeutic drug developments. Targeting Cancer Cell
Metabolism October
1-2, 2012 • Boston, MA Program | Register | Download Brochure
channel
blocker, Compound that reduces or
eliminates the conductance of an ion channel by impeding the movement of ions
through that channel IUPAC Biomolecular Screening See also ion
channels. chemical ligand studies:
Use a more general set of compounds [than
chemical genomics] (often from combinatorial libraries)
to find new targets.
Once the new targets are found, more specific assays
are done. In other words, with the chemical ligands approach, one does blind
screening of chemical libraries using cellular assays. When one gets an
interesting biological effect, one uses the compound to find the target it
modulates. [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 GlaxoWellcome. Martin J.
Valler, Darren Green "Diversity
screening versus focussed screening in drug discovery" Drug Discovery
Today 5(7): July 2000 chemogenomics:
British Journal of Pharmacology, 2007 http://www.nature.com/bjp/journal/v152/n1/full/0707308a.html compound profiling:
Biology
has considerable experience with gene and protein-
centered informatics, but chemistry is at an earlier stage of developing
databases that are truly compound- centric. The historical paradigm of
identifying and optimizing hits for potency, and then looking to evaluate and
optimize for ADME and toxicity properties is quickly shifting to a more parallel
approach that considers ADME/Tox properties at an earlier stage. This concept is
epitomized by methods for differentiating between drug- like and non- drug- like
compounds, the use of which is increasing significantly. Moving compound
profiling earlier means that many more compounds must be assessed, which is both
the value and the challenge of this shift. http://www.healthtech.com/Conferences/2007/cpf/index.asp compound validation: Assays
& screening
cytokine-based therapeutics:
Emerging cytokine-based therapies, and
inhibitors of cytokines and their receptors, represent attractive markets that
have become highly competitive. More than 120 companies are developing over 270
new therapies that either are cytokines, mimic cytokines, or inhibit cytokines
and/or cytokine receptors. Cytokine-Based Therapies and
Inhibitors:R&D Pipelines, Markets, and Strategic Issues September 2011 Table of
Contents | Tables and
Figures |Executive
Summary Related
term: Protein categories: cytokines cytoplasmic and nuclear receptors:
Proteins in the cytoplasm or
nucleus that specifically bind signaling molecules and trigger changes
which influence the behavior of cells. The major groups are the steroid
hormone receptors (RECEPTORS, STEROID), which usually are found in the
cytoplasm, and the thyroid hormone receptors (RECEPTORS, THYROID HORMONE),
which usually are found in the nucleus. Receptors, unlike enzymes,
generally do not catalyze chemical changes in their ligands. MeSH, 1994 deorphanize:
Identification of new ligands for receptors. difficult
targets: drug leads:
small molecule ligands DS Wishart Identifying
putative drug targets and potential drug leads: starting points for virtual
screening and docking. Methods
Mol Biol. 2008;443:333-51.
drug receptors:
Proteins
that bind specific drugs with high affinity and trigger intracellular changes
influencing the behavior of cells. Drug receptors are generally thought to be
receptors for some endogenous substance not otherwise specified. MeSH,
1968 Broader term:
receptors
drug
target, drug targets:
A defined molecule or structure within the
organism, which is linked to a particular disease. For disease intervention, the
drug target may either blocked/inhibited or activated by a drug (small organic
molecules, antibodies, therapeutic proteins). Cytos Biotechnology AG
Glossary of Biological Terms http://www.cytos.com/?id=197 A protein or protein
complex which is implicated in a disease and so has the potential to be affected
by a specific drug. Membrane Protein Structure Initiative Glossary www.mpsi.ac.uk:8080/pims/help/glossary.html
Good drugs are potent and specific; that is, they must have
strong effects on a specific biological pathway and minimal effects on all other
pathways. Confirmation that a compound inhibits the intended target (drug target
validation) and the identification of undesirable secondary effects are among
the main challenges in developing new drugs. Matthew J. Morton et. al, Drug
target validation and identification of secondary drug target effects using DNA
Microarrays, November 1998 4 (11):
1293 - 1301, Nov. 1998 Related terms: molecular drug targets, target families,
targets
Google
"drug target" = about 10,700, Aug, 24, 2002;
about 16,500 June 16, 2003; about 33,500 June 10, 2004; about 586,000 Nov 13,
2006, about 513,000 Aug 18, 2008 [typo in 2006?] drug targeting: A strategy aiming
at the delivery of a compound to a particular tissue of the body. IUPAC
Medicinal Chemistry Related terms: target, target validation.
Narrower terms: gene target, protein target Google = about 6,150, Aug, 24,
2002; about 15,200 June 10, 2004; about 295,000 Nov 13, 2006 DrugBank:
a unique
bioinformatics and cheminformatics resource that combines detailed drug (i.e.
chemical, pharmacological and pharmaceutical) data with comprehensive drug
target (i.e. sequence, structure, and pathway) information. DrugBank is supported by David
Wishart, Departments of Computing
Science & Biological
Sciences, University of Alberta.
DrugBank is also supported by The
Metabolomics Innovation Centre, a Genome Canada-funded core facility serving
the scientific community and industry with world-class expertise and
cutting-edge technologies in metabolomics. druggable
targets:
a protein, peptide, or nucleic acid with
activity that can be modulated by a drug, which can consist of a small molecular
weight chemical compound (SMOL) or a biologic [BIOL) such as an antibody or
recombinant protein (Table 1). Isabella Gashaw, Peter Ellinghaus, Anette Sommer,
Khrusru Asadullah "What makes a good drug target" Drug Discovery Today
2011
Dec;16(23-24):1037-43. Epub 2011 Sep 16. http://www.ncbi.nlm.nih.gov/pubmed/21945861.1
"We have historically fewer innovative
targets per year", said Christopher Lipinski, formerly of Pfizer, showing
that only 24 innovative drugs with new targets have been launched between 1994
and 2001 "Many more druggable targets may have emerged in these eight
years, but there are not enough druglike molecules to match them", Lipinski
said. Horizon Symposia 4 Charting Chemical Space, 2004 . http://www.nature.com/horizon/chemicalspace/highlights/s3_nonspec2.html
efficacy targets:
Molecular targets through which the drug mediates its approved therapeutic
activities. John P Overington et. al How many drug targets are there? Nature
Reviews Drug Discovery, 5 (12): 993-996 Dec 2006 http://www.nature.com/nrd/journal/v5/n12/pdf/nrd2199.pdf
emerging
targets:
The report assesses the issues in
target-based drug discovery and development as well as several specific issues
that are common to these and other complex diseases with high unmet medical
need. … Evaluation of leading emerging targets in terms of signaling pathways
and therapeutic strategies. Insight
Pharma Reports Emerging Targets in Disease with High Unmet Needs, 2006
gene target:
Having identified a potential gene target (and, by inference, its
protein product), one may wish to: (a) sequence the gene in a large number of
affected and normal individuals to identify functional and diagnostic
polymorphisms associated with the disease; or (b) rapidly screen the protein
product for interactions with entities within the chemical portfolio of the
company. Clearly, these needs are addressed by very different approaches and
technological platforms, all of which may be defined as high throughput genomic
strategies.
gene targeting:
The integration of exogenous DNA
into the genome
of an organism at sites where its expression
can be suitably controlled. This integration occurs as a result of homologous
recombination. MeSH, 1995 Google = about 1,080, Aug, 24, 2002;
about 4,070 May 12, 2004; about 96,900 Nov 13, 2006. about 1,110,000 Jan 10,
2011
G-protein-coupled receptors GPCRs:
The GPCR program will continue its tradition of
combining theory with screening and optimization strategies illustrated by case
studies of drug candidates in development. Topics to be covered at this year’s
meeting will include exploiting ligand-biased signaling; receptor
desensitization, internalization and recycling in the context of developing drug
candidates; new tools and technologies (functional screens, label-free assays);
drug discovery Implications of recent GPCR crystal structures ; structure-based
design strategies and therapeutic antibodies.
Current advances in
functional screening methodologies, medicinal chemistry, and structure-based
drug design have generated large increases in the number and diversity of GPCR
drug targets. Furthermore, basic research advances have opened the way for still
further exploitation of this target class. Insight Pharma Reports, GPCRS:
Dawn of a new era? 2008
The largest family of cell surface
receptors involved in SIGNAL TRANSDUCTION. They share a common structure
and signal through HETEROTRIMERIC F- PROTEINS MeSH 2004 "receptors,
g-protein coupled". Narrower terms: orphan G- protein coupled receptors, GPCRomics
histone
deacetylases:
Histone deacetylases (HDACs) have
proven to be a promising target for drug intervention and there are a number of
HDAC inhibitors (HDACi) being tested in the pre-clinical and clinical stages.
HDACi were primarily developed as anti-tumor agents for cancer, but many are now
being explored for treating CNS, immunologic, metabolic, inflammatory and
cardiovascular disorders.
Next-Generation
Histone Deacetylase Inhibitors October 1-2, 2012 • Boston, MA Program | Register | Download Brochure
ion channels:
Gated, ion-selective glycoproteins that traverse membranes. The
stimulus for channel gating can be a membrane potential, drug, transmitter,
cytoplasmic messenger, or a mechanical deformation. Ion channels which are
integral parts of ionotropic neurotransmitter receptors are not included. MeSH
1979 Enable ions to flow
rapidly through membranes in a thermodynamically downhill direction after an
electrical or chemical impulse. IUPAC Bioinorganic
kinase inhibitors: The use of Kinase Inhibitors is moving beyond
the cancer field. The newest developments show lots of promise, especially in
areas such as inflammation and autoimmune diseases. Novel applications for
existing inhibitors are being researched and new targets to develop cancer
therapeutics are being explored. With over 40% of the projects of large pharma
companies in non-oncology areas, there is clearly a need to address the arising
challenges such as resistance, specificity, off-target effects and efficacy.
Novel
Strategies for Kinase Inhibitors October
1-2, 2012 • Boston, MA | Register | Download
Brochure
The
kinase inhibitor field is maturing. This conference is designed to examine the
question of what lays ahead, what is in store for the pharmaceutical industry
and what new avenues are opening up be in regards to technologies and methods
used or in regards to novel targets and therapeutic approaches explored.
kinase
therapeutics:
The field of kinase modulation is one of the most active in
the biopharmaceutical industry. About 20 kinase inhibitors are approved for
marketing in the United States and at least another 250 are in clinical
evaluation. Kinases make up a veritable treasure trove of targets for a variety
of indications. Kinase-Targeted
Therapeutics August 2011Table of
Contents | Tables and
Figures |Executive
Summary
Related terms:
kinase inhibitors, protein
kinases ligand:
In inorganic chemistry the ligands are the atoms or groups of atoms
bound to the central atom (see also coordination). The root
of the word is sometimes converted into the verb to ligate, meaning to
coordinate as a ligand, and the derived participles, ligating and ligated…In
biochemistry the term ligand has been used more widely: if it is possible
or convenient to regard part of a polyatomic molecular entity as central,
then the atoms or groups or molecules bound to that part may be called
ligands. IUPAC Bioinorganic
Pharmacologists
traditionally divide ligands into agonists, which stimulate receptors, and
antagonists, which bind to receptors and block endogenous mediators. According
to the conventional view, the agonist fits into the receptor, like a key fits a
car's ignition, switching on the internal machinery. Antagonists fit the
ignition, but block endogenous transmitters. But recent studies suggest that
many receptors spontaneously activate internal machinery. In these cases, the
receptor is more akin to an accelerator. Mark Greener, Driving Changes in Ligand
Theory, The Scientist 18(15): 32, Aug. 2, 2004 http://www.the-scientist.com/yr2004/aug/research4_040802.html
A molecule that binds
to another molecule, used especially to refer to a small molecule that binds
specifically to a larger molecule, e.g., an antigen binding to an antibody, a
hormone or neurotransmitter binding to a receptor, or a substrate or allosteric
effector binding to an enzyme. Ligands are also molecules that donate or accept
a pair of electrons to form a coordinate covalent bond with the central metal
atom of a coordination complex. (From Dorland, 27th ed) MeSH 1974 Molecules (e.g., drugs) that bind to active sites on proteins. Particularly used of small molecules that bind to larger
molecules. Narrower term: protein ligand; Related terms:
antigen, binding site, enzyme- substrate, hormone- receptor reaction, lock and key
Google = about 301,000 Aug. 13, 2002
about 1, 170,000 Dec. 3, 2003 ligand design:
The design of ligands using structural information
about the target to which they should bind, often by attempting to maximize
the energy of the interaction. IUPAC Computational ligand
gated ion channels:
A subclass of ion
channels that open or close in response to the binding of specific LIGANDS. MeSH
2011
membrane proteins: Protein
categories Important as drug targets
molecular drug targets:
Current Drug Targets aims to cover the latest and most outstanding
developments on the medicinal chemistry and pharmacology of molecular drug
targets e.g. disease specific proteins, receptors, enzymes, genes. Current Drug
Targets scope note, Bentham Science http://www.bentham.org/cdt/index.htm
See also molecular targets Molecular
Pharmacopeia http://www.nature.com/focus/molecularpharmacopoeia/index.html
2006
molecular
profiling: A dynamic new discipline, capable of
generating a global view of mRNA, protein patterns, and DNA alterations in
various cell types and disease processes. MP integrates the expanding
genetic databases from the Human Genome Project with newly developed expression
analysis technologies and holds great promise to help us: Understand the
molecular anatomy of normal cells and cells in various stages of disease.
Develop new diagnostic and therapeutic targets for clinical intervention.
Explain the relationship between genotype and phenotype in humans, which is
still largely unknown. NCI, NIH CGAP "Molecular Profiling" http://cgap-mf.nih.gov/index.html
See also Expression gene & protein molecular
targeted therapy:
Treatments with drugs
which interact with or block synthesis of specific cellular components
characteristic of the individual's disease in order to stop or interrupt the
specific biochemical dysfunction involved in progression of the disease. MeSH
2011
molecular
targeting:
The idea behind molecular
targeting is to design drugs that specifically attack the molecular pathways
that cause disease, without disrupting the normal functions in our cells and
tissues. Drugs developed using this approach can be less toxic and more
effective than current medicines. Molecular Targeting, PhRMA, innovation.org http://www.innovation.org/index.cfm/FutureofInnovation/NextWaveofInnovation/Molecular_Targeting
molecular targets:
Collections of genes organized by pathways and by ontology
(functional classification) permitting aggregate evaluation of anomalies
(overexpression, underexpression, mutation). Molecular Targets, Cancer Molecular
Analysis Project, National Cancer Institute http://cmap.nci.nih.gov/Targets
Can include antibodies, enzymes,
receptors. See also molecular drug targets Google = about 12, 200, Aug. 24, 2002;
about 42, 600 June 10, 2004; about 658,000 Nov. 13, 2006; about 832, 000 May 24,
2007
multi-targeted
therapies: Suites of drugs have been developed that can be used in
combination to treat complex diseases that have multiple causes involving
multiple targets. In addition, it has been found that many successful
small-molecule drugs are promiscuous, i.e., they are single drugs that address
multiple targets. Multitargeted
Therapies June 2011 Table of
Contents | Tables and
Figures
Related terms: promiscuous drugs, promiscuous inhibitors nodal
signaling ligands:
Members of the transforming growth factor superfamily that
play a role in pattern formation and differentiation during the pregastrulation
and GASTRULATION stages of chordate development. Several nodal signaling ligands
are specifically involved in the genesis of left-right asymmetry during
development. The protein group is named after a critical region of the
vertebrate embryo PRIMITIVE STREAK referred to as HENSEN'S NODE. MeSH 2009
nuclear
receptors:
Nuclear receptors are a
super family of intra-cellular receptors present in most animal species. They
mediate the transcriptional responses to metabolic ligands. In humans, 48
nuclear receptors have been identified. These are characterized as belonging to
one of 11 subgroups. The most active targets are the estrogen receptors,
glucocorticoid receptors, and progesterone receptors. Some 13% of drugs approved
for sale in the United States are nuclear receptors with 15 of these drugs in
the top 200 prescribed medicines. These top drugs represented $27.5 billion of
sales revenue in 2009. The top-selling drug in this category is
GlaxoSmithKline’s drug Advair/Seretide with sales of $7.8 billion in 2009. The
major indications for these drugs include asthma, COPD, diabetes type II,
hyperlipidemia, contraception, hormone replacement therapy, prostate cancer, and
osteoporosis. Clearly nuclear receptors are an important class of targets for
pharmaceutical development. Insight Pharma Reports Nuclear
Receptors: The Pipeline Outlook 2010
orphan G-protein-coupled receptors:
GPCRs
with unknown function.
orphan nuclear
receptors:
A broad category of
receptor-like proteins that may play a role in transcriptional-regulation in the
CELL NUCLEUS. Many of these proteins are similar in structure to known NUCLEAR
RECEPTORS but appear to lack a functional ligand-binding domain, while in other
cases the specific ligands have yet to be identified. MeSH 2010
orphan receptors:
Receptor for which no ligands have yet
been identified. Related terms:
deorphan, deorphanize
pharmacophores:
The ensemble of steric and electronic features
that is necessary to ensure the optimal supramolecular interactions with
a specific biological target structure and to trigger (or to block) its
biological response. Does not represent a real molecule or a real association
of functional groups, but a purely abstract concept that accounts for the
common molecular interaction capacities of a group of compounds towards
their target structure. Can be considered as the largest common denominator
shared by a set of active molecules. This definition discards a misuse
often found in the medicinal chemistry literature which consists of naming
as pharmacophores simple chemical functionalities such as guanidines, sulfonamides
or dihydroimidazoles (formerly imidazolines), or typical structural skeletons
such as flavones, phenothiazines, prostaglandins or steroids. Pharmacophoric
descriptors are used to define a pharmacophore, including H- bonding, hydrophobic
and electrostatic interaction sites, defined by atoms, ring centers and
virtual points. IUPAC Medicinal Chemistry
The ensemble of steric and electronic factors which are necessary to
insure supramolecular interactions with a specific biological target structure.
IUPAC Combinatorial Chemistry
A template of chemical properties for an active site of a protein - representing
these properties’ spatial relationship to one another - that theoretically
defines a ligand that would bind to that site.
pharmacophore generation:
A procedure to extract the most important
common structural features relevant for a given biological activity
from a series of molecules with a similar mechanism of action.
IUPAC Computational
phosphoinositide
3 kinase PI3K pathway: Targeting the PI3K Pathway offers opportunities
for therapeutic developments, in a large number of human diseases, such as
cancer, metabolic diseases and inflammation, to name a few. A variety of PI3K
inhibitors have been tested in pre-clinical studies and several have now entered
clinical trials. Advances in Targeting
the PI3K Pathway
October 2-3, 2012 • Boston, MA Program | Register | Download Brochure
promiscuous drugs:
We contend that an ideal drug may be one whose efficacy is based not on the
inhibition of a single target, but rather on the rebalancing of the several
proteins or events, that contribute to the etiology, pathogeneses, and
progression of diseases, i.e., in effect a promiscuous drug....
Corollaries to this argument are that the growing fervor for researching truly
selective drugs may be imprudent when considering the totality of responses; and
that the expensive screening techniques used to discover these, may be both
medically and financially inefficient. Promiscuous drugs compared to selective
drugs (promiscuity can be a virtue) Simon K Mencher and Long G Wang, BMC
Clinical Pharmacology 2005, 5:3 doi:10.1186/1472-6904-5-3 http://www.biomedcentral.com/1472-6904/5/3/abstract
Related term:
selectivity
promiscuous
inhibitors: Nonspecific, seem to be hits in multiple
high- throughput screening (HTS) campaigns, but which turn out to be dead
ends when attempts are made to optimise their activity, a key problem in the
field of HTS. Peter Kirkpatrick, Won't get fooled again, Nature Reviews
Drug Discovery, 4(8): 630, August 2005 rotean ligands:
The literature contains few
examples of ligands that seem to be able to both promote and decrease activity
at the same G-protein-coupled receptors. Such 'protean ligands' — so-
called after the mythical character Proteus, who could adopt any shape he
desired — have been proposed to work by acting as agonists with low efficacy.
They thereby increase the activity of receptors that are basically silent under
resting conditions, but decrease the activity of receptors that have high levels
of ligand- independent, spontaneous (or constitutive) activity. In this model,
protean behaviour therefore depends on having two populations of receptors with
different levels of spontaneous activity. Adam Smith, Adrenoceptor
pharmacology: How the ligand changed its spots Nature Reviews Drug Discovery
1, 569 Aug. 2002 http://www.nature.com/cgi-taf/Gateway.taf?g=5&file=/drugdisc/res_high/articles/nrd885.html&filetype=&_UserReference= protease
inhibitors: Proteases constitute one of the largest potential drug target enzyme
families, with 647 human gene products incorporating protease sequences and
mutated proteases having been identified. In addition, there are many more
proteases found in viruses, bacteria, and parasites, which are also potential
drug targets. The therapeutic promise of protease inhibitors has been most
clearly demonstrated by angiotensin-converting enzyme (ACE) and HIV drugs.
Developments reviewed in this report indicate that more protease inhibitors,
several having significant commercial potential, will reach the market over the
next three to four years. Insight Pharma Reports, Protease
inhibitors: Innovation drives drug pipeline, 2009
Compounds which inhibit
or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES) MeSH 1979
protein families, protein structure: Protein
structure Critical to determining whether a drug target
is druggable
protein kinases:
A family of enzymes that catalyze the conversion of
ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. MeSH,
1980 Broader term: kinases Narrower terms: kinase inhibitors; -Omes & -omics kinome,
kinomics
protein kinase
inhibitors: Agents that inhibit PROTEIN
KINASES. MeSH 2005 Protein-protein interactions (PPI) play a key role in many
biological processes, making them promising targets for drug discovery. Though
inhibition of protein-protein interactions has been challenging due to
binding-site characteristics at the protein-protein interface, there has been
considerable success in recent years. Disease-relevant
intracellular protein-protein interactions occurring at defined cellular sites
possess great potential as drug targets. They permit highly specific
pharmacological interference with defined cellular functions. Drugs targeting
such interactions are likely to act with fewer side effects than conventional
medication influencing whole cell functions. Protein-Protein
Interactions as New Drug Targets Series:
Handbook
of Experimental Pharmacology, Vol. 186 Klussmann, Enno; Scott, John
(Eds.) Springer 2008 http://www.springer.com/biomed/pharmaceutical+science/book/978-3-540-72842-9
A central phenomenon determining the biological pathways found in living
systems. They are the focus of many proteomic technologies being developed
today to decipher an intricate network of interactions. Correlated changes in protein expression
(such as co- regulation or sequential regulation) provide
a hint that two proteins may be interacting with each other.
Play a major role in almost all relevant physiological
processes occurring in living organisms, including DNA replication and
transcription, RNA splicing, protein biosynthesis, and signal
transduction. Related terms: Proteomics
interaction proteomics, yeast two-hybrid.
protein
targets:
The purpose of the "PDB
ligands" link is to give, at a glance, a quick way of determining if
compounds in the selected SOM cluster have any "known" protein targets
and if any homologous human proteins exist. The PDB ligands link from each
cluster page provides connections to structural data as deposited in the Protein
Data Bank (PBD). PDB Ligands Summary http://spheroid.ncifcrf.gov/spheroid/ManPages/ManPdbLigands.cfm
Google = about 2,340 Aug. 24, 2002;
about 3,790 Aug. 27, 2003; about 7,710 June 10, 2004; 133,000 Nov 13, 2004;
about 154,000 May 25, 2007, about 318,000 Jan 10 2011
proteomimetics--
small molecule: The interaction between proteins
is fundamental to many receptor- ligand, enzyme- substrate, and protein- protein
interactions that have been linked to human disease states. Given the large
number of novel protein targets emerging from the genome and the dearth of small
molecules known to bind to and antagonize these targets, the challenge presented
to the pharmaceutical industry is in the identification of novel agents
effecting these novel targets. Traditional screening methods can be augmented by
directed discovery efforts that seek to capture the essence of a protein's
binding epitope in the context of a small molecule. Folding@home
glossary, Stanford Univ. http://www.stanford.edu/group/pandegroup/folding/education/P.html
Related term:
protein small molecule interactions Google = about 43
July 14, 2004, about 327 Oct. 25, 2006
proteonomics:
Expression systems that can rapidly produce high levels
of recombinant proteins are a critical link between the discovery of new genes
and the identification of targets and molecules for drug development. Advances
in the baculovirus expression technology makes it the system of choice in the
emerging field of proteonomics where rapid production and high yields of
biologically active complex proteins are essential in the discovery of new drug
targets, vaccines, and biotherapeutics. Folding@home
glossary, Stanford Univ. http://www.stanford.edu/group/pandegroup/folding/education/P.html Google = about 593 Sept. 18, 2002;
about 805 Aug 18, 2003; about 3,530 July 14, 2004; about 10,200 Nov. 5, 2005;
about 17,300 Nov 10, 2006 Related term: proteomics
prototypes: First
in class compounds usually directed at a specific molecular target. (Note that
we have adapted the term for use in a broader sense to replace the term lead
compound, which arguably loses some of its meaning after the4 lead optimization
process.) Insight
Pharma Reports, Backup Compound Strategies: Best Practices for Reducing Phase II
Risk, 2007 receptor:
A protein or a protein complex in or on a cell that
specifically recognizes and binds to a compound acting as a molecular messenger (neurotransmitter,
hormone, lymphokine, lectin, drug, etc.). In a broader sense, the term receptor
is often used as a synonym for any specific (as opposed to non- specific such as binding to plasma proteins) drug
binding site, also including nucleic acids such as DNA. IUPAC
Computational Narrower terms: amino acid receptors,
cell surface receptors, drug receptors, receptor mapping In
silico & Molecular
modeling; Related
terms: Cell biology
ligand;
receptors,
cytoplasmic and nuclear:
Proteins in the cytoplasm or
nucleus that specifically bind signaling molecules and trigger changes which
influence the behavior of cells. The major groups are the steroid hormone
receptors (RECEPTORS, STEROID), which usually are found in the cytoplasm, and
the thyroid hormone receptors (RECEPTORS, THYROID HORMONE), which usually are
found in the nucleus. Receptors, unlike enzymes, generally do not catalyze
chemical changes in their ligands. MeSH 1994 See also nuclear
hormone receptors
receptor
tyrosine kinase like orphan receptors:
A family of
cell surface receptors that were originally identified by their structural
homology to neurotropic TYROSINE KINASES and referred to as orphan receptors
because the associated ligand and signaling pathways were unknown. Evidence for
the functionality of these proteins has been established by experiments showing
that disruption of the orphan receptor genes results in developmental defects.
MeSH 2010 selectivity: The
word selectivity describes a drug's ability to affect a particular cell
population in preference to others. As part of the current state of art in the
search for new therapeutic agents, the property of selectivity is a mode of
action thought to have a high degree of desirability.... Selectivity is
generally a worthy property in a drug because a drug having high selectivity may
have a dramatic effect when there is a single agent that can be targeted against
the appropriate molecular-driver involved in the pathogenesis of a
disease. Promiscuous drugs compared to selective drugs (promiscuity can be
a virtue) Simon K Mencher and Long G Wang, BMC Clinical Pharmacology 2005, 5:3
doi:10.1186/1472-6904-5-3 http://www.biomedcentral.com/1472-6904/5/3/abstract
Related term:
promiscuous drugs target: Molecules in the body that may be addressed by drugs to produce a therapeutic
effect. (Also used to refer to the material -- DNA or RNA - that one exposes to
the probes on a microarray so that hybridization can be measured subsequently. A molecule that may interact with a drug or drug candidate. Pharmaceutical
industry expert Jürgen Drews (now chairman of International
Biomedicine Management Partners, Inc. and formerly of Hoffman La Roche) has
noted that all drug therapy is currently based on 500 molecular targets. Target in a drug screening context often means drug target.
See also target (hybridization). Narrower terms: disease targets, gene target, tractable
targets. Related terms: drug targeting, target
validation
target
amplification:
Increasing the amount of target
nucleic acid, providing more template for the label, to achieve improved detection.
Useful for low levels of expression or abundance or very small sample
sizes. Target amplification increases the amount of target nucleic acid,
providing more template for the label and therefore more signal. This
approach helps overcome problems associated with low expression of some genes or
small sample sizes. The kinetics of the amplification step, however, must be
reproduced exactly in these approaches; otherwise, changes observed on the array
could be the result of differential amplification. Target- amplification
processes include PCR, Rolling Circle Amplification RCA, Strand Displacement
Amplification SDA. Related terms: Gene
amplification & PCR
target characterization:
Requires evidence that the potential
target actually plays a role in the disease process, and that modulation of the
target may ameliorate or reverse a disease phenotype. A potential
target which may be a validated target. Related terms: target identification, target qualification, target validation
target credentialing:
Identification of
target molecules, evidence of modification of the target molecule, and
measurement of desired effect. Clinical Radioresistance of Primary Glial Tumors,
Radiation Biology, Progress Review groups, NINDS http://www.ninds.nih.gov/find_people/groups/brain_tumor_prg/RadiationBiology.htm
There are now agents in clinical trial or about to
enter clinical trial that have been designed against a specific molecular
target. The putative target for a number of these agents has also been
associated with radioresistance. Such agents will be evaluated for their ability
to modify tumor cell radiosensitivity. Critical to these studies will be the
establishing a causal relationship between the agent-induced modification of the
target and radiosensitization. This will serve to validate (or invalidate) a
given molecule as a target for radiosensitization (target credentialing) and
establish a "marker" for the use in the potential design of a clinical
trial. Although initial studies will be performed using tumor cell lines and
normal cells in vitro, agents found to be effective in vitro will then be
evaluated using in vivo models. Molecular Radiation Therapeutics Branch,
National Cancer Institute http://www3.cancer.gov/rrp/mrtb.html
target evaluation:
The shift from
traditional to genomics-and proteomics-based drug discovery has fundamentally
changed the way researchers view the subject of targets. After decades of
focusing on a few hundred relatively well-characterized therapeutic targets,
drug developers are now finding that the genomics revolution has presented them
with the opposite dilemma: thousands of prospective targets about which little
is known. Insight Pharma Reports, Powering Discovery
through Target Evaluation: Moving beyond the validation paradigm, 2005 http://www.insightpharmareports.com/reports/2005/52_TargetValidation/overview.asp
Can cover the range of target- winnowing
strategies, from target identification to target validation. Google = about 1,650, Aug. 24, 2002;
about 1,780 Aug. 27, 2003 [not all relevant]; about 2,780 June 10, 2004; about
34,500 Nov 13, 2006; about 38,100 June 25, 2007
target families/target family:
The majority of pharmaceutically relevant
drug targets cluster into densely populated target families, thus offering a
novel approach that complements the currently favoured screening paradigm in
medicinal chemistry. This approach uses a privileged structure concept whereby
molecular masterkeys are developed that account for a target family wide
structural or functional commonality. Numerous lead compounds, based on
multipurpose privileged structures, can be generated that address a variety of
targets from a gene family of interest, irrespective of therapeutic area. Medicinal chemistry of targeted directed masterkeys, Drug Discovery
Today, 2003 http://www.ncbi.nlm.nih.gov/pubmed/12927511 Although the sheer numbers of potential targets
uncovered through genomics- based methods create an enormous need for target-
identification and validation technologies, these numbers also make
possible new opportunities, which go way beyond what is possible via traditional
drug discovery methods. The
limited number of target families addressed by traditional drug discovery
methods suggests that these methods are "boxed in" and unable to
create the numbers of novel drugs (three to five per year for major companies)
that will be necessary to meet pharmaceutical companies' business goals.
target gene families:
small molecule leads — identified by
virtue of their interaction with a single member of a gene family — are used
to study the biological role of other members of that family, the function of
which is unknown. Chemogenomics: an emerging strategy for rapid target and drug
discovery, Markus Bredel & Edgar Jacoby, Nature Reviews Genetics 5, 262-275
April 2004 http://www.nature.com/nrg/journal/v5/n4/box/nrg1317_BX1.html
See also Chemistry chemogenomics
Google = about 95 Nov
13, 2006; about 5,210 June 25, 2007, about 4,370 Oct 8, 2007
target glut:
While an individual company may have four or five times
as many targets under analysis now than it did five years ago, most of those
targets are completely new or poorly understood. Lack of annotation for genomic
data is a major problem in choosing the best targets to pursue for drug
development. Related terms: target identification,
target screening, target validation; Bioinformatics: information overload; Drug
discovery & development druggable genome
target haplotype: Pharmacogenomics target hopping: Directed crossover of a compound to a new target.
"Chemical genomics advances drug discovery" Genetic Engineering News
22 (13):1 , July 2002 www.messebasel.ch/miptec/
.%5Cpdf%5CGEN_July_Aldridge.pdf Related term?:
Assays lead hopping Chemistry scaffold
hopping target (hybridization):
There are currently at least two nomenclature systems for referring
to hybridization partners. Both use common terms ‘probes’ and ‘targets’
… With respect to the nucleic acids whose entwining represents the hybridization
reaction, the identify of one is defined - it tends to be tethered to the
solid phase, making up the microarray itself. The identity of the other
is revealed by hybridization. The strategy of the ‘standard’ microarray
therefore parallels that of a reverse dot- blot, in which the probe is immobilized.
For this reason, authors of articles appearing in this supplement have
been encouraged to describe the tethered nucleic acid as ‘probe’
and the free nucleic acid as ‘target’. Chipping Forecast supplement
"A note on nomenclature" Nature Genetics 21 (1s): 1 Jan 1999 Has this been
standardized yet? See also the note under probes- microarray Microarrays A molecule (usually a protein gene
product, but sometimes
a DNA sequence, or, in the case of antisense drugs, an mRNA) that may interact
with a drug or drug candidate. Instead of target, some people use sample [in the context of microarrays]
. We find fault with this usage, though we fall into it occasionally, because
the same word often refers to the biological material from which mRNA was
extracted (e.g., tissue or serum from patients or laboratory animals). In
addition, sample is an important term in statistics, where it has
a completely different meaning. (It means the subset of a population that is
surveyed for the purpose of estimating properties of the entire population.). target
identification: Identifying molecules that clearly play a
role in a disease process. Target identification methods provide a finer
degree of detail than target screening and require
evidence that the gene/ protein is correlated with the disease. Google
= about 14,800, Aug. 24, 2002; about 22,900 Aug. 26, 2003; about 37,600
June 10, 2004; about 494,000 Nov 13, 2006 target
labelling: Targets for arrays are labelled representations
of cellular mRNA pools. Typically reverse transcription from an oligo-dT
primer is used … Frequently total RNA pools (rather than mRNA selected
on oligo-dT) are labelled, to maximize the amount of message that can be
obtained from a given amount of tissue. DJ Duggan et al “Expression
profiling using cDNA microarrays” Nature Genetics 21(1s): 10- 14, Jan 1999 Google
Aug. 26, 2003 "target labelling" = about 80; about 136 June 10,
2004; about 530 Nov 13, 2006 "target
labeling" = about 418; Aug 26, 2003; about 943 June 10, 2004; about 19,800
Nov 13, 2006 target
molecules: Target genes or target proteins.
Google = about 6,480, Aug. 24, 2002'
about 11,300 Aug. 26, 2003; about 21,000 June 10, 2004; about 473,000 Nov 13,
2006
target prioritization: Target prioritization is
today a bottleneck as a result of the new genomics based drug discovery. Given
the exponential increase in targets provided by the new technologies as gene
expression analysis, no company can afford to advance all of the targets
identified. Our Markets: The Drug Discovery Industry, InNetics http://innetics.com/markets.htm target product
profiles: A tool for planning in the
development phase of R&D projects. Insight Pharma
Reports, Backup
Compound Strategies: Best Practices for Reducing Phase II Risk, 2007 target proteins:
The project TargId at GMD SCAI focuses on methods to address the
arguably most urgent problem: the elucidation of the origins and mechanisms of
human diseases, culminating in the identification of potential drug target
proteins. Identification of Drug Target Proteins, by Alexander Zien, Robert
Küffner, Theo Mevissen, Ralf Zimmer and Thomas Lengauer ERCIM News No.43 -
October 2000 http://www.ercim.org/publication/Ercim_News/enw43/zien.html target qualification:
Qualifying that potential
target genes or proteins clearly have a role in a disease process. target screening: Identifying
molecules that may be associated with a disease process (e.g., upregulation of a
particular gene identified through gene expression analysis). CHA, Cambridge
Healthtech Advisors Model
Animal Systems: Emerging Applications and Commercial Opportunities in Drug
Discovery and Development, report, 2004 Related terms: target glut, target identification, target validation
Google = about 799, Aug. 24, 2002;
about 1,230 Aug. 26, 2003; about 2,050 June 10, 2004; about 73,600 Nov 13, 2006 target
selection: The main purpose of the Bioinformatics
Core (BIC) is to select the target for research. The goals of BIC are to develop
complete high throughput technology for structural genomics beginning with high
throughput computational selection of target proteins, followed by robotic
expression and crystallization and fully automated data collection and structure
solution. List of Important Definitions, JCSG Joint Center for Structural
Genomics http://www.jcsg.org/help/robohelp/Definitions/Target_Selection.htm
http://www.nigms.nih.gov/News/Reports/psi_targetselect.htm target
space:
Structure-Based Drug Design (SBDD) has been in
use within the pharmaceutical industry for over twenty-five years. SBDD
continues to play an important role in drug discovery, design and optimization.
Moreover, with the development of sophisticated biophysical and computational
methodologies SBDD is impacting hit identification and ‘hit to lead’
optimization approaches across the industry. Therapeutic
Target Space DVD 2010
target validation:
Target validation involves demonstrating that a molecular target is critically involved in a
disease process, and that modulation of the target is likely to have a
therapeutic effect. CHA, Cambridge Healthtech Advisors Model
Animal Systems: Emerging Applications and Commercial Opportunities in Drug
Discovery and Development, report, 2004 Determining which among genes or proteins being
investigated as potential drug targets lead to phenotypic changes when
modulated, suggesting that they may have value as therapeutic targets. Many people would say
a target is truly validated only after proven effective in human trials. The definition of target validation is clearly evolving, can be seen as
"slippery" and clearly means different things to different people.
Google = about 6,580, Aug. 24, 2002;
about 10,300 Aug. 26, 2003; about 17,600 June 10, 2004, about 281,000
April 24, 2006; about 282,000 Nov 13, 2006; about 244,000 May 25, 2007
target validation technologies:
A number of technologies including
downregulation of gene expression (gene knockdown, antisense, ribozymes and
zinc
finger proteins), protein inhibition (phage libraries and antibodies),
cellular
assays, chemical genetics, and combinatorial biology are linked with target
validation. The integration of various technologies is another
challenge.
targeted gene
repair:
A technique which uses synthetic
oligonucleotides to direct the cell's inherent DNA repair system to correct a
mutation at a specific site in an episome or chromosome. targeted
therapy: A type of treatment that uses drugs or other substances capable of
interfering with targeting molecules that are needed for carcinogenesis and
tumor growth. The benefit of targeted therapy is that cancer cells are attacked
without harming normal cells. TARGET Therapeutically Applicable Research to Generate Effective
Treatments The
goal of targeted therapeutics is to create drugs that by the specificity of
their design and delivery will make them more effective in treating disease and
less toxic. tractable targets:
Targets from families such as 7TM receptors,
ion channels, kinases and proteases which have produced previous hits.
Martin J. Valler, Darren Green "Diversity screening versus focussed
screening in drug discovery " Drug
Discovery Today 5(7): July 2000 Related terms: druggable, low
hanging fruits, pharmaceutically tractable
ubiquitin pathway:
Drugs
targeting the ubiquitin system are still relatively new; the first approval by
the FDA happened in 2003. Ubiquitination (ligases) as well as deubiquitination (deubiquitylating
enzymes (DUB’s) play key roles in cellular signal transduction pathways and
offer numerous opportunities for therapeutic interventions for treating diseases
such as cancer, inflammation and metabolic diseases. However, in order to bring
more ubiquitin targeting drugs to the market, some challenges need to be
addressed. Targeting the Ubiquitin
Pathway October
1-2, 2012 • Boston, MA Program | Register | Download Brochure
Bibliograph Insight
Pharma Reports Drug targets series http://www.insightpharmareports.com/Reports/All.aspx?s=TRGS
How
to look for other unfamiliar terms
IUPAC definitions are reprinted with the permission of
the International Union of Pure and Applied Chemistry.
Evolving Terminologies for Emerging Technologies
Comments? Questions?
Revisions? Mary Chitty mchitty@healthtech.com
Last revised July 12, 2012
<%end if%>
Biology Functional
genomics Pharmaceutical
biology SNPs and other genetic variations
Chemistry Assays & Screening Cheminformatics
Libraries & Synthesis
Pharmaceutical chemistry
Informatics: Drug discovery informatics
Bioinformatics Cheminformatics
Genomic Informatics Protein Informatics
Technologies Gene
amplification & PCR
Genomic Technologies Metabolic
profiling Microarrays &
protein arrays Molecular
Imaging Protein Technologies Sequencing
binding,
competitive: The interaction of two or
more substrates or ligands with the same binding site. The displacement of one
by the other is used in quantitative and selective affinity measurements. MeSH
1973
Display of Difficult Targets
February 19-20, 2012 • San
Francisco, CA Program | Register | Download Brochure
Discovery on Target October 1-3, 2012 • Boston, MA Program | Register | Download Brochure
disease targets:
The critical
strategy for a pharmaceutical company going forward is one that uses pharmacogenomics
and biomedical informatics to
better define disease targets. ... Pharmacogenomics is key to gaining a
better definition of disease, a better stratification of patients and
improved disease staging. Until these are clear, and until some form of
biomedical informatics is put into place, therapeutic design is going to be
flawed by poorly defined targets. Broader term: target
Related term: drug target Google = about 3,250, Aug, 24, 2002;
about 12,900 June 10, 2004; about 104,000 Nov 13, 2006, about 41,900 June 25,
2009
How many drug targets are there? John P Overington, et. al,
Nature Reviews Drug Discovery, 2006 http://www.nature.com/nrd/journal/v5/n12/pdf/nrd2199.pdf
GPCR-Based Drug Discovery October 1-2, 2012 • Boston,
MA Program | Register | Download Brochure
histone methyltransferases: Histone
methyltransferases (HMTs) and demethylases (HDMs) have rapidly emerged within
the suite of epigenetic modifiers as new and promising classes of therapeutic
targets. Recent genetic discoveries of HMT and HDM anomalies in various cancer
types provide unique validation for selective and tumor-specific targeting of
these enzymes. Clinical intervention is becoming increasingly feasible, but
deciphering their role in complex disease, developing robust screening and
hit-finding approaches for inhibitors, and assessing patient-specific efficacy
and safety of novel therapies remain challenging. Targeting Histone Methyltransferases and Demethylases October 2-3, 2012 •
Boston, MA Program | Register | Download Brochure 
Ion
channels as therapeutic targets, Discovery on Target Nov 2010 Boston MA order
CD 
Ion
Channel Modulator Pipelines
Insight
Pharma Reports, September 2009
Table
of Contents | Tables
and Figures | Executive
Summary See also channel blockers
Next-Gen Kinase Inhibitors June
4-6, 2012 • Cambridge, MA Program | Register | Download
Brochure
Google = about 82, Aug, 24, 2002;
about 201 June 10, 2004; about 2,060 Nov 13, 2006, about 938 Aug 17, 2008
The PI3K/Akt/mTOR signaling cascade serves many physiological and
pathophysiological functions and is of major importance in a broad array of
cancers. This has stimulated substantial interest in identifying and developing
modulators of this pathway. The PI3K/Akt/mTOR Pathway November 2011Table of Contents | Tables and Figures |Executive Summary
Protein kinase evolution,
SUGEN,
2002 http://www.kinase.com/evolution/
protein- protein interactions: Protein-Protein
Interaction as Drug Targets
April
18-19, 2012 • San Diego, CA Program | Register | Download
Brochure
retargeting:
A
conceptual breakthrough in gene therapy would be gene transfer vector that could
be systemically applied, allowing targeted gene transfer into a predetermined
cell type. C. Haynes et. al, Modified envelope glycoproteins to retarget
retroviral vectors, Current Gene Therapy 3(5): 405- 410, Oct. 2003 Related term: Molecular
Medicine gene therapy
Google = about 666, Aug. 24, 2002;
about 1,780 June 10, 2004; about 26,100 Nov 13, 2006
Google = about 9, Aug. 24, 2002; about 24 June 10,
2004; about 49 Nov 13, 2006; about 71 Oct 8, 2007, about 198 Jan 11 2011
Google = about 27 Aug.
26, 2003; about 30, June 10, 2004; about 70 Apr. 27, 2005; about 485 Nov 13,
2006; about 284 Nov 16, 2007
See also target
[above] Related terms: Drug
discovery & development Sample and sample
preparation
Google = about 422, Aug. 24, 2002;
about 476 Aug. 26, 2003; about 517 June 10, 2004; about 911 Nov 13, 2006; about
11,000 May 25, 2007
Google = about 8,610, Aug. 24, 2002;
about 20,000 Aug. 26, 2003; about 36,900 June 10, 2004; about 740,000 Nov 13,
2006, about 863,000 Oct 8, 2007
MeSH 2007
Therapeutic Targets
Database: http://xin.cz3.nus.edu.sg/group/cjttd/ttd.asp
Computational Science Dept, Science Faculty, National University of
Singapore
Google = about 175
June 10, 2004; about 586 Nov 13, 2006
IUPAC International Union of Pure and Applied Chemistry, Glossary of Terms
used in Bioinorganic Chemistry, Recommendations, 1997. 450+ definitions. http://www.chem.qmw.ac.uk/iupac/bioinorg/
IUPAC Glossary of Terms
used in Biomolecular Screening, IUPAC Recommendations 2008 provisional
recommendations about 150 terms defined
IUPAC International Union of Pure and Applied Chemistry, Glossary of Medicinal
Chemistry, 1998. 100+ terms. http://www.chem.qmw.ac.uk/iupac/medchem
MeSH Medical Subject Headings, (PubMed Browser) National Library
of Medicine, Revised annually. 250,000 entry terms, 19,000 main headings. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=MeSH&term=
Drug targets Conferences http://www.healthtech.com/Conferences/Upcoming.aspx?s=TRGS
Discovery on Target http://www.healthtech.com/DOT/
Drug targets CDs, DVDs http://www.healthtech.com/Conferences/CompactDiscs.aspx?s=TRGS
Drug targets Short courses http://www.healthtech.com/Conferences_Upcoming_ShortCourses.aspx?s=TRGS
Insight Pharma Reports
Cytokine
Therapeutics: A Vibrant Pipeline and Active Approved Market Full
Report | Executive
Summary 2007
Insight Pharma Reports GPCRs: Dawn of a New Era? Full
Report | Executive
Summary 2008
Insight Pharma Reports Ion
Channel Modulator Pipelines 2009
Insight Pharma Reports Kinase
Therapeutics: Pipeline Assessment and Commercial Prospects 2010
Insight Pharma Reports Nuclear
Receptors: The Pipeline Outlook 2010
Insight Pharma Reports Protease Inhibitors: Innovation Drives Drug Pipeline Full
Report | Executive
Summary 2009
Alpha
glossary index
