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SCOPE NOTE: Drug targets include Chimeric Antigen Receptors CAR-T, GPCRs G
protein coupled receptors, ion channels, kinases, membrane proteins, protease
inhibitors, ubiquitin
Drug targets A prerequisite
for counting the number of targets is defining what a target is.
Indeed, this is the crucial, most difficult and also most arbitrary
part of the present approach. For the purpose of this paper, we
consider a target to be a molecular structure (chemically definable by
at least a molecular mass) that will undergo a specific interaction
with chemicals that we call drugs because they are administered to
treat or diagnose a disease. The interaction has a connection with the
clinical effect(s). This definition implies several constraints.
First, the medicinal goal excludes pharmacological and
biochemical tools from the present approach. Second, a major
constraint is a lack of technique. Life, including disease, is
dynamic, but as we do not yet directly observe the interactions of
drugs and targets, and only partly notice the subsequent biochemical
'ripples' they produce; we are generally limited to 'still life' (for
example, X-ray crystal structures) and to treating targets as static
objects. In the case of G-protein-coupled receptors (GPCRs), the
pharmaceutically most useful class of receptors, a re-organization of
the protein after drug binding was derived
from
biochemical data4,
but such approaches are still in their infancy. Nature
Reviews Drug Discovery 5, 821-834 (October
2006) doi:10.1038/nrd2132 OPINION: Drugs,
their targets and the nature and number of drug targets Peter Imming1,
Christian Sinning1 &
Achim Meyer1
http://www.nature.com/nrd/journal/v5/n10/full/nrd2132.htm
Agonist Immunotherapy Targets
April 11-12, 2019 Boston, MA
Program |
Stepping on the Gas with Costimulatory Agents
The immunotherapies industry is currently
dominated by antagonist antibodies such as PD-1 and CTLA-4. However, it is
clear that antagonists alone are not enough to elicit response in the
majority of patients, hence a rising interest in agonists targets.
CHI’s Agonist Immunotherapy Targets conference will examine these modalities and their
treating disease. Agonists showing the most promise, including OX40, CD27,
GITR, and 4-1BB, will be covered in clinical case studies by examining the
data as well as the biology and mechanisms. Emerging agonists, including
TNFR receptors, ICOS, STING, and VISTA will also be discussed. Focus will
be given throughout to potential combination immunotherapies to ensure
durable antitumor response.
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.
autophagy:
Emerging ubiquiting & autophagy targets
September 17-18 2019 Boston, MA
https://www.discoveryontarget.com/ubiquitin-autophagy
biological
target:
A biological target is anything within a living
organism to which some other entity (like an endogenous ligand or
a drug)
is directed and/or binds, resulting in a change in its behavior or function.
Examples of common classes of biological targets are proteins and nucleic
acids. The
definition is context-dependent, and can refer to the biological target of a pharmacologically
active drug compound,
the receptor target of a hormone (like insulin),
or some other target of an external stimulus. Biological targets are most
commonly proteins such as enzymes, ion
channels, and receptors.
Wikipedia accessed 2018 Aug 22
https://en.wikipedia.org/wiki/Biological_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.
channel
blocker, Compound that reduces or
eliminates the conductance of an ion channel by impeding the movement of ions
through that channel
Note: Dihydropyridine
antagonists such as nifedipine, which also block the conductance of some L-type
calcium channels, are not classified as channel blockers since their action is
to inhibit channel gating. Example:
verapamil, which blocks the conductance of some L-type calcium channels.
Constrained Peptides and Macrocyclics
September 26-27, 2018 Boston, MA
Program |
Constrained peptides
covers the progress and challenges of accessing new chemical space – the
middle space – to find molecules with drug potential that are bigger than
small molecules but smaller than biologics. The hope is that these
middle-sized molecules are big enough for more specific interactions with
protein-protein interaction surfaces but small enough to penetrate the
cell, reach intracellular drug targets and be orally bioavailable.
However, theory is still meeting practice. Researchers continue to refine
the ’rules’ and properties for the best design of this class of molecules
which mainly consist of constrained peptides and synthetic macrocyclics.
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
drug
target, drug targets:
An
unspoken industry rule alleges that at least 50% of published studies from
academic laboratories cannot be repeated in an industrial setting, wrote
venture capitalist Bruce Booth in a recent blog
post.
A first-of-a-kind analysis of Bayer's internal efforts to validate 'new drug
target' claims now not only supports this view but suggests that 50% may be an
underestimate; the company's in-house experimental data do not match literature
claims in 65% of target-validation projects, leading to project discontinuation.
Nature
Reviews Drug Discovery 10, 643-644 (September
2011) | doi:10.1038/nrd3545
Reliability of 'new drug target' claims called into question Asher
Mullard
http://www.nature.com/nrd/journal/v10/n9/full/nrd3545.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. Narrower terms: gene target, protein target.
targets
drug targeting:
Drug delivery
DrugBank:
The DrugBank database is a unique bioinformatics
and cheminformatics resource that combines detailed drug data with comprehensive
drug target information.
http://www.drugbank.ca/ 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 See
also druggability: Drug discovery
Compare undruggable targets 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
epigenetic
targets:
In the light of increasing knowledge on the role epigenetic factors play
in disease, it is now becoming apparent that epigenetics could be ideal
therapeutic targets - particularly taking into consideration that many of
these epigenetic factors are reversible. Epigenetic drugs are incredibly
potent and can help reverse abnormal gene expression that can result in
various diseases. BioMedCentral Blog 2016
https://blogs.biomedcentral.com/on-biology/2016/09/08/future-epigenetic-drugs/
Histone deacetylases (HDAC) are a class of enzymes that remove acetyl
groups from an amino acid on a histone. This is important because DNA is
wrapped around histones, and DNA expression is regulated by acetylation
and de-acetylation. … HDACs are downstream targets of signaling pathways,
and signaling molecules (kinases in particular) regulate the activities of
HDACs through multiple diverse pathways. HDACs in turn modulate different
signaling pathways by deacetylation of histones and non-histones or
through as yet unknown mechanisms. Proper coordination of cell signaling
with histone/non-histone deacetylation is critical to precisely regulate
both gene expression and a number of transcription independent events.
HDAC proteins are vital regulators of fundamental cellular events, such as
cell cycle progression, differentiation, and tumorigenesis. Abnormal HDACs
can contribute to many different human diseases including cancer,
neurodegenerative disorders, cardiac hypertrophy, and pulmonary
diseases. Edward Seto, Xiang-Jiao Yang, in Handbook
of Cell Signaling (Second Edition), 2010
https://www.sciencedirect.com/topics/neuroscience/histone-deacetylase
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
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".
histone demethylases:
The genetic abnormalities that drive
tumorigenesis are usually coupled with epigenetic alterations, such as DNA
methylation and aberrant histone modifications, which may help oncogenic
drivers accelerate cancer progression, metastasis, and therapy resistance.
The discovery of histone demethylases has provided us new insight for
understanding the epigenetic landscape of the chromatin environment of
cancer cells. This review aims to summarize the current knowledge on the
human histone lysine demethylases and their functions in cancers, and
recent advances in development of small molecule inhibitors to target
histone demethylases in cancer treatment. D'Oto A, Tian QW, Davidoff AM,
Yang J. Histone demethylases and their roles in cancer epigenetics. J Med
Oncol Ther. 2016;1(2):34-40.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279889/
Inflammation
and Autoimmune
Inhibitors
April 10-11, 2019 • San Diego, CA Program | Efforts to find and develop small
molecule-based drug agents for combatting inflammation and
autoimmune-related conditions is intensifying in the drug discovery
industry. The first oral-based treatment for rheumatoid arthritis, a small
molecule JAK kinase inhibitor, was launched a few years ago. The focus on
oral-based anti-inflammatory agents (which are mostly small molecules
though some macrocyclics and constrained peptides can also penetrate
cells) is not only because oral-based therapeutics afford greater patient
convenience, but also because of the rapidly accumulating scientific
knowledge of the myriad of intracellular molecules involved in
inflammation and autoimmune-related conditions.
Kinase Inhibitor Discovery
September 18-19, 2019 Boston, MA
Program |
Lead Generation Strategies
September 17-18, 2019 Boston, MA
Program
Finding
new chemical entities with high drug potential as fast as possible has
always been the goal in early drug discovery. Often the process is
separated into two steps: ‘hit’ generation which focuses on quickly
finding large numbers of compounds with questionable drug potential
followed by secondary screens to reveal promising, high-drug potential
leads. Recently though the two processes are often combined because of
automation and biophysical advances that enable smaller numbers but higher
quality drug leads to be found from the start.
ligand:
Pharmaceutical biology
ligand
gated ion channels: A subclass of ion
channels that open or close in response to the binding of specific LIGANDS. MeSH
2011
macrocycle:
Cyclic macromolecule or a macromolecular cyclic portion of a
macromolecule.
Note 1: A cyclic macromolecule has no end-groups
but may nevertheless be regarded as a chain.
Note 2: In the
literature, the term macrocycle is sometimes used for molecules of low
relative molecular mass that would not be considered macromolecules.
IUPAC. Compendium of Polymer Terminology and Nomenclature, IUPAC
Recommendations 2008 (the “Purple Book”) (PDF).
RSC Publishing, Cambridge, UK
macrocyclics:
Constrained Peptides and Macrocyclics
September 26-27, 2018 Boston, MA
Program |
Macrocyclics covers the progress and challenges
of accessing new chemical space – the middle space – to find molecules
with drug potential that are bigger than small molecules but smaller than
biologics. The hope is that these middle-sized molecules are big enough
for more specific interactions with protein-protein interaction surfaces
but small enough to penetrate the cell, reach intracellular drug targets
and be orally bioavailable. However, theory is still meeting practice.
Researchers continue to refine the ’rules’ and properties for the best
design of this class of molecules which mainly consist of constrained
peptides and synthetic macrocyclics.
Macrocyclics & Constrained Peptides
Cell-Penetrating,
Bigger Molecules for Oral-Based Therapeutics
APRIL 10-11, 2019 San Diego CA
Synthetic macrocyclics and constrained peptides are of growing interest in
the pharmaceutical industry because they are expanding the chemical space
that can be explored for new therapies. This new class is considered
‘ideal’ because its medium size and ring structure are supposed to combine
the best properties of biologics and small molecules. They are small
enough to get in cells but large enough for specific interactions with
more targets such as protein-protein interactions (PPIs) and their cyclic
nature enhances their solubility. Some compounds are advancing in clinical
trials. However, challenges still remain such as solubility and
cell-penetration. Medicinal chemists continue to refine design ideas.
Directed-evolution approaches to create libraries based on macrocyclics
are also being applied.
https://www.drugdiscoverychemistry.com/Macrocyclics/
membrane proteins:
Antibodies Against Membrane
Protein Targets-Part 1
September 17-18, 2019 Boston, MA
Program |
Antibodies Against Membrane
Protein Targets-Part 2
September 18-19, 2019 Boston, MA
Program |
As the
pharmaceutical and biotech industries increasingly shift attention to
biologics, much more attention is being paid to the prospect of
membrane-bound proteins as drug targets for antibodies and other protein
scaffolds. For the large GPCR and ion channel target classes, biologics
offer improved selectivity, an alternative for targets with known function
that have not been amenable to small molecule drugs and the potential for
using antibodies for the targeted delivery of therapeutics. However, for
the field to advance, fundamental challenges in optimizing antigen quality
and presentation, discovery methodologies, protein engineering and target
identification must be resolved.
membrane
proteomics:
Membrane proteins
perform some of the most important functions in the cell, including the
regulation of cell signaling through surface receptors, cell-cell interactions,
and the intracellular compartmentalization of organelles. Recent developments in
proteomic strategies have focused on the inclusion of membrane proteins in
high-throughput analyses. While slow and steady progress continues to be made in
gel-based technologies, significant advances have been reported in non-gel
shotgun methods using liquid chromatography coupled to mass spectrometry
(LC/MS). Wu CC, Yates John R, The
application of mass spectrometry to membrane proteomics Nature Biotechnology
21(3): 262- 267, March 2003 Related terms: membrane proteins, membranomics
microbiome:
Targeting the Microbiome
September 27-28, 2018 Boston, MA
Program |
Basic
and applied biomedical research from the Human Microbiome Project and
other independent studies prove that a disruption of a stable microbiome
ecosystem results in dysbiosis. This imbalance leads to chronic disease
and health conditions. There is great promise in correlating the
microbiome compositions with these diseases and using the microbiome as a
tool for therapeutic development.
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
profiling:
Elsevier
https://www.sciencedirect.com/topics/medicine-and-dentistry/molecular-profiling
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 targets:
Molecular targets are cellular or tissue structures that are intended to be
visualized by means of molecular imaging. Different biological structures can
potentially serve as imaging targets, ranging from proteins to DNA and RNA.
Springer, Molecular targets
https://link.springer.com/referenceworkentry/10.1007%2F978-3-540-35280-8_1580
See also molecular drug targets
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. Related terms: promiscuous drugs, promiscuous inhibitors
nuclear hormone receptor proteins:
form a class of ligand activated
proteins that, when bound to specific sequences of DNA serve as on-off
switches for transcription within the cell nucleus. These switches control
the development and differentiation of skin, bone and behavioral centers
in the brain, as well as the continual regulation of reproductive tissues.
Univ of Illinois Urbana Champaign Theoretical and Computational Bio
Physics, Nuclear Hormone Receptors
https://www.ks.uiuc.edu/Research/pro_DNA/ster_horm_rec/
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.
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
PROTACS
Proteolysis-targeting
chimeric molecules:
Sept 2019 Boston MA a group of engineered hetero-bifunctional chemical
entities that bind to the target and ligase to mediate ubiquitination and
subsequent protein degradation. Like PROTACs, other chemical entities and
molecular glues, using varied mechanisms-of-action, are being developed to
trigger targeted protein degradation. These approaches have a lot of
potential in seeking out previously “undruggable” protein targets for
applications in drug discovery and for developing new therapeutic
modalities. However, some challenges do exist in terms of stability,
biodistribution and penetration of these molecules in
vivo. https://www.discoveryontarget.com/PROTAC-protein-degradation
protease
inhibitors: Compounds which inhibit
or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES) MeSH 1979
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.
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
Targeting PPIs and
Nucleic Acid Complexes for Therapeutic Interventions
APRIL 9-10, 2019 San Diego CA
Modulating disease-relevant protein-protein interactions (PPIs) or
protein-nucleic acid complexes by chemical agents is a strategy for
discovering new compounds with therapeutic potential. However
intracellular PPIs are harder to rationally design drugs against or screen
in a traditional high-throughput biochemical assay than are traditional
intracellular targets such as enzymes. PPIs lack an active site to target.
Nevertheless, PPI-targeted drug discovery is moving forward. In fact, the
first PPI-targeted drug (against the BCL2 complex) was launched a few
years ago for cancer and a few more PPIs are the targets of drug
candidates in clinical development.
https://www.drugdiscoverychemistry.com/Protein-Protein-Interactions/
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.
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
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:
Biologics gene therapy
RNA as a drug
target: September 18-19 2019
Boston MA
RNA molecules are crucial for delivering cellular information and genetic
regulation, but until recently, the drug discovery world has emphasized
protein drug targets. Our lack of knowledge in RNA biology prevented us
from exploring possibilities of RNA drug targets, but with recent advances
in technologies such as sequencing, new therapeutic strategies are being
explored. https://www.discoveryontarget.com/RNA-Therapeutics-Targets
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
engagement
Determining the
biological functions of proteins requires selective tools to perturb their
expression and/or activity in living systems. Molecular biology methods,
such as targeted gene disruption and RNA interference, are ubiquitous and
fairly straightforward methods to achieve this goal. Small-molecule probes
offer complementary and, in some ways, superior tools for interrogating
proteins and pathways because they can provide greater spatiotemporal
control over protein function and can perturb this parameter without
concomitant changes in protein expression1.
This latter feature, of course, also means that the effect of
small-molecules on protein function can rarely be inferred from simple
protein abundance measurements like Western blotting. Alternative assays
must be enlisted to confirm that a small molecule interacts with its
intended protein target in a living system, a parameter that is referred
to as target engagement. 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 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 Related terms:
Assays lead hopping Chemistry scaffold
hopping 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:
Target Identification &
Validation-Part 1
September 26-27, 2018 Boston, MA
Program |
Finding
novel, druggable targets for therapeutic intervention remains a top priority for
the pharma/biotech industry, especially when it comes to building a robust drug
discovery pipeline. It also remains a formidable challenge and companies
continue to invest a lot of time and resources in identifying and validating
good drug targets to pursue. What are the challenges in target discovery? What
tools and strategies are being used and how well are they working? What’s being
done to ensure that validated targets lead to better and safer therapies?
Target Identification &
Validation-Part 2
September 27-28, 2018 Boston, MA
Program
Target
identification of biologically active molecules such as natural products,
synthetic small molecules, peptides, and oligonucleotides mainly relies on
affinity chromatography, activity-based probes, or photoaffinity labeling (PAL).
Amongst them, activity-based probes and PAL have offered great advantages in
target identification technology due to their ability to form covalent bonds
with the corresponding targets. Activity-based probe technology mainly relies on
the chemical reactivity of the target proteins, thereby limiting the majority of
the biological targets to enzymes or proteins which display reactive residues at
the probe-binding site. Molecules 2013, 18(9),
10425- 10451;
doi: 10.3390/molecules180910425 Review
Recent Advances in Target Characterization and Identification by
Photoaffinity Probes Jitapa
Sumranjit 1,2 and Sang
J. Chung http://www.mdpi.com/1420-3049/18/9/10425 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.
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
target
molecules: Target genes or target proteins.
target prioritization:
Drug target prioritization by
perturbed gene expression and network information ,2015
https://www.nature.com/articles/srep17417
target prioritization TDR
database http://tdrtargets.org/ The
TDR Targets project seeks to exploit the availability of diverse datasets to
facilitate the identification and prioritization of drugs and drug targets in
neglected disease pathogens. 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
target validation:
The
identification and validation of disease-causing target genes is an essential
first step in drug discovery and development. Genomics and proteomics
technologies have already begun to uncover novel functional pathways and
therapeutic targets in several human diseases such as cancers and autoimmunity.
Also, bioinformatics approaches have highlighted several key targets and
functional networks. In contrast to gene-profiling approaches,
phenotype-oriented target identification allows direct link between the genetic
alterations and a disease phenotype. Therefore, identified genes are more likely
to be a cause rather than a consequence of the disease. Once a gene target or a
mechanistic pathway is identified, the next step is to demonstrate that it does
play a critical role in disease initiation, perpetuation, or both. Methods
Mol Biol. 2007;360:1-12. Main approaches to target discovery and
validation. Sioud
M. http://www.ncbi.nlm.nih.gov/pubmed/17172722 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. 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 means different things to different people.
target validation technologies:
A range of
strategies exists for modulating gene expression in vitro and in vivo. These
strategies include the use of antibodies, negative dominant controls, antisense
oligonucleotides, ribozymes, and small-interfering RNAs. In contrast to in vitro
assays, mouse reverse genetics such as knockout phenotypes has become a powerful
approach for deciphering gene function and target validation in the context of
mammalian physiology. In addition to disease-causing genes, the identification
of antigens that stimulate both arms of the immune system is the major goal for
effective vaccine development. Methods
Mol Biol. 2007;360:1-12. Main approaches to target discovery and
validation. Sioud
M. http://www.ncbi.nlm.nih.gov/pubmed/17172722 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 to identify and
attack specific types of cancer cells with less harm to normal cells. Some
targeted therapies block the action of certain enzymes, proteins, or other
molecules involved in the growth and spread of cancer cells. Other types
of targeted therapies help the immune system kill cancer cells or deliver
toxic substances directly to cancer cells and kill them. Targeted therapy
may have fewer side effects than other types of cancer treatment. Most
targeted therapies are either small molecule drugs or monoclonal
antibodies. NCI
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 [as a drug target]:
Screening for ubiquitin ligase substrates: Identification of E3
ligase substrates is critical to understand its implication in human
diseases since deregulation of E3-substrate interactions are often served
as major cause in many. To overcome the limitation of mechanism used to
identify the substrates of the E3 Ubiquitin Ligase, a system called the
'Global Protein Stability (GPS) Profiling' was developed in 2008.[112] This
high-throughput system made use of reporter proteins fused with thousands
of potential substrates independently. By inhibition of the ligase
activity (through the making of Cul1 dominant negative thus renders
ubiquitination not to occur), increased reporter activity shows that the
identified substrates are being accumulated. This approach added a large
number of new substrates to the list of E3 ligase substrates….Finding a
specific molecule that selectively inhibits the activity of a certain E3
ligase and/or the protein-protein interactions implicated in the disease
remains as one of the important and expanding research area. Moreover, as
ubiquitination is a multi-step process with various players and
intermediate forms, consideration of the much complex interactions between
components needs to be taken heavily into account while designing the
small molecule inhibitors.[97]
Wikipedia accessed 2018 Nov 5
https://en.wikipedia.org/wiki/Ubiquitin#As_a_drug_target
ubiquitin:
Emerging ubiquiting & autophagy targets
September 17-18 2019 Boston, MA
https://www.discoveryontarget.com/ubiquitin-autophagy
A
potentially much larger percentage of proteins could be made druggable if protein–protein
interactions could be disrupted by small molecules. However the
majority of these interactions occur between relatively flat surfaces of
the interacting protein partners and it is very difficult for small
molecules to bind with high affinity to these surfaces.[23][24] Hence
these types of binding sites on proteins are generally thought to be
undruggable but there has been some progress (by 2009) targeting these
sites.[25][26]
Wikipedia accessed 2019 June 24
http://en.wikipedia.org/wiki/Druggability
virtual
target screening: Computational
methods involving virtual screening could potentially be employed to discover
new biomolecular targets for an individual molecule of interest (MOI). However,
existing scoring functions may not accurately differentiate proteins to which
the MOI binds from a larger set of macromolecules in a protein structural
database. An MOI will most likely have varying degrees of predicted binding
affinities to many protein targets. However, correctly interpreting a docking
score as a hit for the MOI docked to any individual protein can be problematic.
In our method, which we term "Virtual Target Screening (VTS)", a set
of small drug-like molecules are docked against each structure in the protein
library to produce benchmark statistics. This calibration provides a reference
for each protein so that hits can be identified for an MOI. VTS can then be used
as tool for: drug repositioning (repurposing), specificity and toxicity testing,
identifying potential metabolites, probing protein structures for allosteric
sites, and testing focused libraries (collection of MOIs with similar
chemotypes) for selectivity. J
Chem Inf Model. 2012 Aug 27;52(8):2192-203. doi: 10.1021/ci300073m.
Epub 2012 Jul 23. Virtual target screening: validation using kinase inhibitors. Santiago
DN, Pevzner
Y, Durand
AA, Tran
M, Scheerer
RR, Daniel
K, Sung
SS, Woodcock
HL, Guida
WC, Brooks WH. http://www.ncbi.nlm.nih.gov/pubmed/22747098
Drug targets resources Royal Society of
Chemistry, Drug and target mapping
https://www.rcsb.org/pages/help/DrugPDBMapping
Drug targets Conferences http://www.healthtech.com/Conferences/Upcoming.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 MSLS
mchitty@healthtech.com
Last revised
June 24, 2019
Related glossaries include: Drug
discovery & development Molecular
Diagnostics
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
Discovery
on Target Sept 16-19, 2019 • Boston, MA Program Novel drug
targets and technologies
for mall molecules and biologics.
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
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
G-protein-coupled receptors GPCRs:
GPCR-Based Drug Discovery
September 18-19, 2019 Boston, MA
Program |
G
protein-coupled receptors (GPCRs), which relay chemical signals such as hormones
from outside to the inside of cells, are the targets of approximately a third of
the medicines on the market today. However, many of the GPCR-acting medicines
were discovered decades or more ago, without today’s more detailed knowledge
about and tools for working with GPCRs. The receptors span the membrane seven
times, thus are challenging to solubilize and study in vitro. Recent biophysical
advances though have bypassed some of the membrane-embedded challenges and
enabled GPCR structural insights and spurred new screening applications. The
receptors’ signaling complexities due to their ability to couple to a variety of
G proteins (biased signaling) are also now more understood and capitalized upon
to design more selective drugs
GPCRs &
Membrane Proteins
Designing Drugs Targeted
at Proteins with Multiple Membrane-Spanning Domains
Narrower terms: orphan G- protein coupled receptors, GPCRomics
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: Kinase
Inhibitor Chemistry
APRIL 9-10, 2019 San diego CA
Over the past decade, kinase drug discovery has resulted in the rapid
development of a new generation of anti-cancer drugs. As kinase inhibitor
discovery remains an active area for a significant portion of all efforts,
developers have found new ways to expand into a deeper portion of target
space within the human kinome, moved beyond cancer and into chronic
disease indications such as CNS disorders, as well as shifted toward
allosteric modulation and harnessing slow-off or irreversible compounds.
https://www.drugdiscoverychemistry.com/Kinase-Inhibitor-Chemistry/
Proteins which are found in membranes including cellular and intracellular
membranes. They consist of two types, peripheral and integral proteins.
They include most membrane- associated enzymes, antigenic proteins,
transport proteins, and drug, hormone, and lectin receptors. MeSH, 1977
Narrower terms: integral proteins, intrinsic proteins, membrane
transport proteins, peripheral proteins extrinsic proteins,
Molecular
Pharmacopeia
http://www.nature.com/focus/molecularpharmacopoeia/index.html
2006
NF-kappa B:
Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two
DNA- binding subunits: NF-kappa B1 and relA. MeSH, 1991
Wikipedia
https://en.wikipedia.org/wiki/NF-%CE%BAB
Nature News nf-kappaB
https://www.nature.com/subjects/nf-kappab Related
terms: cytokines
Protein kinase evolution,
SUGEN,
2012 http://www.kinase.com/evolution/
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004587/
target evaluation:
Can cover the range of target- winnowing
strategies, from target identification to target validation.
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 (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
See also target
[above] Related terms: Drug
discovery & development Sample and sample
preparation
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.
MeSH 2007
Therapeutic Targets
Database: National University of Singapore http://bidd.nus.edu.sg/group/cjttd/
ubiquitin proteosome system:
Targeting
the Ubiquitin-Proteasome System
Novel Tools and Compounds
to Modulate DUBs, Ligases and Other Proteins
APRIL 10-11, 2019 SAN Diego CA
The ubiquitin-proteasome system (UPS) is a complex, highly regulated network of
proteins that is responsible for intracellular protein degradation and turnover.
Advances in our understanding of the role and molecular mechanisms of the UPS
components in disease and the development of high quality chemical tools and
inhibitors have turned the previously “undruggable” UPS targets into an exciting
opportunity for small molecule drug intervention. Over the past years, we have
seen the development of a new generation of deubiquitinating enzymes (DUBs) and
proteasome inhibitors poised for clinical development, as well as the discovery
of novel inhibitors for disrupting the protein-protein interactions in ligases
and hijacking the UPS for targeted protein degradation.
https://www.drugdiscoverychemistry.com/ubiquitin-inhibitors/
undruggable targets:
Only 2% of human proteins interact
with currently approved drugs. Furthermore, it is estimated that only
10-15% of human proteins are disease modifying while only 10-15% are
druggable (there is no correlation between the two), meaning that only
between 1-2.25% of disease modifying proteins are likely to be
druggable. Hence it appears that the number of new undiscovered drug
targets is very limited.[20][21][22]
Harding SD, Sharman JL, Faccenda E, Southan C, Pawson AJ, Ireland S, Gray AJG,
Bruce L, Alexander SPH, Anderton S, Bryant C, Davenport AP, Doerig C, Fabbro D,
Levi-Schaffer F, Spedding M, Davies JA; NC-IUPHAR. (2018) The
IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the
new guide to IMMUNOPHARMACOLOGY. Nucl.
Acids Res. 46 (Issue
D1): D1091-D1106. doi: 10.1093/nar/gkx112
http://www.guidetopharmacology.org/
An
expert-driven guide to pharmacological targets and the substances that act on
them. Glossary
http://www.guidetopharmacology.org/helpPage.jsp#glossary
Discovery on Target
http://www.discoveryontarget.com/
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
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