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Current
Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 5, Number 3, September 2008
Contents
High-Throughput Screening Assays to Discover Small-Molecule
Inhibitors of Protein Interactions Pp. 190-199
Pierre Colas
[Abstract]
Activity Based Chemical Proteomics: Profiling
Proteases as Drug Targets Pp. 200-212
William Percy Heal, Sasala Roshinie Wickramasinghe
and Edward William Tate
[Abstract]
Current Topics of Organic and Biological
Chemistry of Annonaceous Acetogenins and their Synthetic Mimics
Pp. 213-229
Hidefumi Makabe, Hiroyuki Konno and
Hideto Miyoshi
[Abstract]
SNP Technologies for Drug Discovery:
A Current Review Pp. 230-235
Joanne Voisey and Charles Phillip
Morris
[Abstract]
Advances in Drug Discovery to Assess
Cholinergic Neurotransmission: A Systematic Review Pp.
236-249
Vitor F. Ferreira, David R. da Rocha, Kátia
G. Lima Araújo and Wilson C. Santos
[Abstract]
Translation of New Technologies: From
Basic Research to Drug iscovery and Development Pp.
250-262
Nirmala Bhogal and Michael Balls
[Abstract]
RANKL/RANK/OPG: Key Therapeutic Target
in Bone Oncology Pp. 263-268
Kosei Ando, Kanji Mori, Francoise Rédini
and Dominique Heymann
[Abstract]
Abstracts
[Back to top]
High-Throughput Screening Assays to Discover Small-Molecule
Inhibitors of Protein Interactions
Pierre Colas
The availability of large collections of small-molecule inhibitors
of protein interactions would bear a tremendous impact both
on academic and therapeutic research. The past recent years
have seen a marked acceleration in the discovery of protein
interaction inhibitors, through structure-based drug design
but mostly through screening efforts. This article attempts
to review the impressive number and variety of in vitro
and cellular screening assays that have been developed and,
for most of them, used successfully to identify small-molecule
inhibitors of protein interactions. Various strategies aimed
at improving hit rates are also reviewed, and future challenges
to improve discovery success rates are discussed. The growing
list of protein interaction inhibitors and the large arsenal
of screening methods, now available to most laboratories or
screening facilities, will probably convince an increasing
number of academic and industrial scientists that protein
interactions are more druggable than once feared, and that
their respective research interests would greatly benefit
from the discovery of protein interaction inhibitors.
[Back to top]
Activity Based Chemical Proteomics: Profiling Proteases as
Drug Targets
William Percy Heal, Sasala Roshinie Wickramasinghe
and Edward William Tate
The pivotal role of proteases in many diseases has generated
considerable interest in their basic biology, and in the potential
to target them for chemotherapy. Although fundamental to the
initiation and progression of diseases such as cancer, diabetes,
arthritis and malaria, in many cases their precise role remains
unknown. Activity based chemical proteomics-an emerging field
involving a combination of organic synthesis, biochemistry,
cell biology, biophysics and bioinformatics-allows the detection,
visualisation and activity quantification of whole families
or selected sub-sets of proteases based upon their substrate
specificity. This approach can be applied for drug target/lead
identification and validation, the fundamentals of drug discovery.
The activity-based probes discussed in this review contain
three key features; a ‘warhead’ (binds irreversibly
but selectively to the active site), a ‘tag’ (allowing
enzyme ‘handling’, with a combination of fluorescent,
affinity and/or radio labels), and a linker region between
warhead and tag. From the design and synthesis of the linker
arise some of the latest developments discussed here; not
only can the physical properties (e.g., solubility,
localisation) of the probe be tuned, but the inclusion of
a cleavable moiety allows selective removal of tagged enzyme
from affinity beads etc. The design and synthesis
of recently reported probes is discussed, including modular
assembly of highly versatile probes via solid phase
synthesis. Recent applications of activity-based protein profiling
to specific proteases (serine, threonine, cysteine and metalloproteases)
are reviewed as are demonstrations of their use in the study
of disease function in cancer and malaria.
[Back to top]
Current Topics of Organic and Biological Chemistry of Annonaceous
Acetogenins and their Synthetic Mimics
Hidefumi Makabe, Hiroyuki Konno and
Hideto Miyoshi
Annonaceous acetogenins are a large family of natural polyketides.
So far, more than 430 compounds have been isolated. Biologically,
they are among the most potent of the known inhibitors of
complex I (NADH ubiquinone oxidoreductase) in mitochondrial
electron transfer system. Herein, we would like to conduct
an overview on the progress of the total synthesis, structural
revisions, structure activity relationship for the inhibition
of complex I, and action mechanism.
[Back to top]
SNP Technologies for Drug Discovery: A Current Review
Joanne Voisey and Charles Phillip
Morris
Single nucleotide polymorphisms (SNPs) are unique genetic
differences between individuals that contribute in significant
ways to the determination of human variation including physical
characteristics like height and appearance as well as less
obvious traits such as personality, behaviour and disease
susceptibility. SNPs can also significantly influence responses
to pharmacotherapy and whether drugs will produce adverse
reactions. The development of new drugs can be made far cheaper
and more rapid by selecting participants in drug trials based
on their genetically determined response to drugs. Technology
that can rapidly and inexpensively genotype thousands of samples
for thousands of SNPs at a time is therefore in high demand.
With the completion of the human genome project, about 12
million true SNPs have been identified to date. However, most
have not yet been associated with disease susceptibility or
drug response. Testing for the appropriate drug response SNPs
in a patient requiring treatment would enable individualised
therapy with the right drug and dose administered correctly
the first time. Many pharmaceutical companies are also interested
in identifying SNPs associated with polygenic traits so novel
therapeutic targets can be discovered. This review focuses
on technologies that can be used for genotyping known SNPs
as well as for the discovery of novel SNPs associated with
drug response.
[Back to top]
Advances in Drug Discovery to Assess Cholinergic Neurotransmission:
A Systematic Review
Vitor F. Ferreira, David R. da Rocha, Kátia
G. Lima Araújo and Wilson C. Santos
Neurotransmission is essential to physiological processes
of cellular communication. The search for new molecules that
may influence neurotransmission systems is an open field with
possible impact on several pathophysiological conditions or
diseases: Alzheimer’s disease, Parkinsonism and myasthenia
gravis, etc. The present review describes the most important
aspects of cholinergic neu rotransmission, as well as natural
and synthetic compounds that, as clinical or experimental
drugs, are able to influence this transmission. The pharmacological
effects of substances that bind to muscarinic or nicotinic
cholinergic receptors, along with their corresponding affinities
will also be presented.
[Back to top]
Translation of New Technologies: From Basic Research to Drug
iscovery and Development
Nirmala Bhogal and Michael Balls
Despite increasing investment in drug discovery and development,
only around one in every ten new medicinal products that progresses
to clinical testing ever reach from the registration stage.
Approximately half of all drug failures are attributed to
problems with efficacy and toxicity not anticipated from preclinical
studies. As a consequence, the pharmaceutical industry is
adopting a much more flexible and multi-disciplinary approach
to drug discovery and development. Indeed, the line between
basic and applied science is constantly being eroded, not
least because of the increasing sophistication of therapeutic
procedures and the complexity of the diseases that they aim
to treat. Here, we look at the new technologies that are being
explored as a way of reducing drug attrition rates and the
development of chemical drugs and biotherapeutics. Specifically,
we will consider the ways in which genomics and related disciplines,
engineered cell-based and microfluidics systems, and nanotechnologies
are being developed and used alongside in silico platforms
during early drug pharmacokinetics and toxicity studies. The
way in which information from such systems biology-oriented
approaches can be integrated with information from animal
based preclinical safety, toxicological and pharmacological
studies on investigative medicinal products is considered,
in view of its current and possible impact on clinical trial
design.
[Back to top]
RANKL/RANK/OPG: Key Therapeutic Target in Bone Oncology
Kosei Ando, Kanji Mori, Francoise Rédini
and Dominique Heymann
Cancer is one of the major leading causes of death all
over the world. Primary and secondary bone tumors can significantly
deteriorate the quality of life (QOL) and the activity of
daily living (ADL) of the patients. These unwelcome diseases
become a social and economic burden seriously. Thus, more
effective therapies for both primary and secondary bone tumors
are actually required. Bone homeostasis depends on the strictly
balanced activities between bone formation by osteoblasts
and bone resorption by osteoclasts. Imbalance of bone formation
and resorption results in various bone diseases. Both primary
and secondary bone tumors develop in the unique environment
bone, it is therefore necessary to understand bone cell biology
in tumoral bone environment. Recent findings strongly revealed
the significant involvement of the receptor activator of nuclear
factor κB
ligand (RANKL)/RANK/osteoprotegerin (OPG) triad, the key regulators
of bone remodeling in bone oncology. Indeed, RANKL/RANK blocking
successfully prevented the development of bone metastases.
Furthermore, some cancer cells express RANK which is involved
in tumor cell migration. Thus, the regulation of this triad
will be a rational, encouraged therapeutic hot spot in bone
oncology. In this review, we summarize the accumulating knowledge
of the RANKL/RANK/OPG triad and discuss about its therapeutic
capability in primary and secondary bone tumors.
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