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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 25, 2006
Contents
Recent Progress in Medicinal Chemistry of D4 Agonists
Pp. 2981-2993
Cécile Enguehard-Gueiffier and Alain Gueiffier
[Abstract]
Docking and Scoring – Theoretically Easy, Practically
Impossible? Pp. 2995-3003
B. Coupez and R.A. Lewis
[Abstract]
The Gut Microbiota and Lipid Metabolism: Implications
for Human Health and Coronary Heart Disease Pp. 3005-3021
F. Fava, J.A. Lovegrove, R. Gitau, K.G. Jackson
and K.M. Tuohy
[Abstract]
Generation and Maintenance of Mucosal Memory
B Cell Responses Pp. 3023-3037
M. Vajdy
[Abstract]
Modulation of Hepatocyte Apoptosis: Cross-talk
Between Bile Acids and Nuclear Steroid Receptors Pp.
3039-3051
S. Solá, J.D. Amaral, M.M. Aranha, C.J.
Steer and C.M.P. Rodrigues
[Abstract]
Protein S-100B - A Prognostic Marker for Cerebral
Damage Pp. 3053-3060
Mark Stroick, Marc Fatar, Andreas Ragoschke-Schumm, Klaus
Faßbender,Thomas Bertsch and Michael G. Hennerici
[Abstract]
Nucleic Acids Modulate Autoimmunity Through
Nucleic- Acid-Specific Toll-Like Receptors Pp. 3061-3067
Prashant S. Patole and Hans-Joachim Anders
[Abstract]
Serotonin Involvement in the Basal Ganglia Pathophysiology:
Could the 5-HT2C Receptor be a New Target for Therapeutic
Strategies? Pp. 3069-3081
Giuseppe Di Giovanni, Vincenzo Di Matteo, Massimo Pierucci,
Arcangelo Benigno and Ennio Esposito
[Abstract]
Identifying Accessible Sites in RNA: The First
Step in Designing Antisense Reagents Pp. 3083-3103
Wei-Hua Pan and Gary A. Clawson
[Abstract]
Targeting Airway Inflammation: Novel Therapies
for the Treatment of Asthma Pp. 3105-3111
Garry M. Walsh
[Abstract]
Abstracts
[Back to top]
Recent Progress in Medicinal Chemistry of D4
Agonists
Cécile Enguehard-Gueiffier and
Alain Gueiffier
In the last decades, the physiological
and pharmacological properties of dopamine receptors were
controversial principally because of the lack of selective
ligand for some receptor subtypes. Since 1997, some specific
D4 agonists have been described and have allowed
a therapeutic approach. We report here, compounds described
as D4 agonist and when available the SAR. The major
studies for physiological implications and their potential
biological applications are also reported and principally
their interest in erectile dysfunction.
[Back to top]
Docking and Scoring – Theoretically
Easy, Practically Impossible?
B. Coupez and R.A. Lewis
Structure-based Drug Design (SBDD)
is an essential part of the modern medicinal chemistry, and
has led to the acceleration of many projects, and even to
drugs on the market. Programs that perform docking and scoring
of ligands to receptors are powerful tools in the drug designer’s
armoury that enhance the process of SBDD. They are even deployed
on the desktop of many bench chemists. It is timely to review
the state of the art, to understand how good our docking programs
are, and what are the issues. In this review we would like
to provide a guide around the reliable aspects of docking
and scoring and the associated pitfalls aiming at an audience
of medicinal chemists rather than modellers.
For convenience, we will divide the review into two parts:
docking and scoring. Docking concerns the preparation of the
receptor and the ligand(s), the sampling of conformational
space and stereochemistry (if appropriate). Scoring concerns
the evaluation of all of the ligand-receptor poses generated
by docking. The two processes are not truly independent, and
this will be discussed here in detail.
The preparation of the receptor and ligand(s) before docking
requires great care. For the receptor, issues of protonation,
tautomerisation and hydration are key, and we will discuss
current approaches to these issues. Even more important is
the degree of sampling: can the algorithms reproduce what
is observed experimentally? If they can, are the scoring algorithms
good enough to recognise this pose as the best? Do the scores
correlate with observed binding affinity? How does local knowledge
of the target (for example hinge-binding to a kinase) affect
the accuracy of the predictions? We will review the key findings
from several evaluation studies and present conclusions about
when and how to interpret and trust the results of docking
and scoring. Finally, we will present an outline of some of
the latest developments in the area of scoring functions.
[Back to top]
The Gut Microbiota and Lipid
Metabolism: Implications for Human Health and Coronary Heart
Disease
F. Fava, J.A. Lovegrove, R. Gitau, K.G. Jackson
and K.M. Tuohy
Coronary heart disease (CHD) is the
leading cause of mortality in Western societies, affecting
about one third of the population before their seventieth
year. Over the past decades modifiable risk factors of CHD
have been identified, including smoking and diet. These factors
when altered can have a significant impact on an individuals’
risk of developing CHD, their overall health and quality of
life. There is strong evidence suggesting that dietary intake
of plant foods rich in fibre and polyphenolic compounds, effectively
lowers the risk of developing CHD. However, the efficacy of
these foods often appears to be greater than the sum of their
recognised biologically active parts. Here we discuss the
hypothesis that beneficial metabolic and vascular effects
of dietary fibre and plant polyphenols are due to an up regulation
of the colon-systemic metabolic axis by these compounds. Fibres
and many polyphenols are converted into biologically active
compounds by the colonic microbiota. This microbiota imparts
great metabolic versatility and dynamism, with many of their
reductive or hydrolytic activities appearing complementary
to oxidative or conjugative human metabolism. Understanding
these microbial activities is central to determining the role
of different dietary components in preventing or beneficially
impacting on the impaired lipid metabolism and vascular dysfunction
that typifies CHD and type II diabetes. This approach lays
the foundation for rational selection of health promoting
foods, rational target driven design of functional foods,
and provides an essential thus-far, overlooked, dynamic to
our understanding of how foods recognised as “healthy”
impact on the human metabonome.
[Back to top]
Generation and Maintenance
of Mucosal Memory B Cell Responses
M. Vajdy
The mucosal immune system comprises
B cells that can mount potent antibody responses against a
variety of mucosal pathogens. Mucosal B cell responses can
play a decisive role in protection against mucosal pathogens.
Induction of mucosal B cell responses can be achieved through
mucosal vaccination. However, mucosal administration of antigens
without the use of adjuvants or delivery systems can lead
to tolerance rather than immunity, and thus considerable efforts
have been focused on development of effective immunopotentiating
adjuvants and delivery systems. However, because the ultimate
goal of vaccination is the induction and maintenance of immunological
memory, the underlying mechanisms for induction of long-term
mucosal B cell memory need to be analyzed for the selection
of appropriate adjuvants. Moreover, as the antigen unspecific
innate immune system invoked by adjuvants contributes significantly
to the development of antigen-specific B cell responses, and
presumably B cell memory, optimal interaction of B cells with
cellular components of the innate immune system is required.
To better understand the mechanisms that lead to the induction
of mucosal antibody responses, antibodies against single epitopes
from specific B cell clones as opposed to antibodies against
large poly proteins from multiple B cell clones can be studied.
This review deals with the concept of mucosal B cell memory
with special emphasis on efforts to devise effective prophylactic
or therapeutic vaccines.
[Back to top]
Modulation of Hepatocyte
Apoptosis: Cross-talk Between Bile Acids and Nuclear Steroid
Receptors
S. Solá, J.D. Amaral, M.M. Aranha, C.J.
Steer and C.M.P. Rodrigues
The efficient removal of unwanted
cells, such as senescent, damaged, mutated or infected cells
is crucial for the maintenance of normal liver function. In
fact, apoptosis has emerged as a potential contributor to
the pathogenesis of a number of hepatic disorders, such as
viral hepatitis, autoimmune diseases, ethanol-induced injury,
cholestasis, and hepatocellular carcinoma. In contrast to
the effect of cytotoxic bile acids in the liver, ursodeoxycholic
acid (UDCA) has increasingly been used for the treatment of
various liver disorders. The clinical efficacy of this hydrophilic
bile acid was first recognized by its use in traditional Asian
medicine. However, many studies have subsequently confirmed
that UDCA improves liver function by three major mechanisms
of action, including protection of cholangiocytes against
the cytotoxicity of hydrophobic bile acids, stimulation of
hepatobiliary secretion, and inhibition of liver cell apoptosis.
UDCA acts as a potent inhibitor of the classical mitochondrial
pathway of apoptosis, but also interferes with alternate and
upstream molecular targets such as the E2F-1/p53 pathway.
Together, there is growing evidence that this hydrophilic
bile acid may modulate gene expression to prevent cell death.
Curiously, as a cholesterol-derived molecule, UDCA interacts
with nuclear steroid receptors, such as the glucocorticoid
receptor. Nuclear steroid receptors play crucial roles in
mediating steroid hormone signaling involved in many biological
processes, including apoptosis. Here, we review the anti-apoptotic
mechanisms of UDCA in hepatic cells, and discuss a potential
involvement of nuclear steroid receptors in mediating the
survival effects of UDCA.
[Back to top]
Protein S-100B - A Prognostic
Marker for Cerebral Damage
Mark Stroick, Marc Fatar, Andreas Ragoschke-Schumm, Klaus
Faßbender,Thomas Bertsch and Michael G. Hennerici
The assessment of S-100B in acute
neurological disorders such as global hypoxia, ischaemic or
haemorrhagic stroke and traumatic brain injury reflects severity
of symptoms and outcome. However, the temporal profile of
S-100B release depends on topography, intensity and pathophysiology
of the damage e.g. immediate release after traumatic brain
injury following the acute destruction of neuronal tissue
or delayed release after ischaemic stroke in which gradual
breakdown of the blood-brain barrier plays a crucial role.
In chronic brain diseases, knowledge about the clinical value
of quantification of S-100B is scarce and further evaluations
are needed. This review considers both conditions for S-100B
measurement and illustrates advantages and limitations in
comparison with clinical and neuroimaging data.
[Back to top]
Nucleic Acids Modulate Autoimmunity
Through Nucleic- Acid-Specific Toll-Like Receptors
Prashant S. Patole and Hans-Joachim Anders
Autoimmune diseases are believed
to develop mainly from three factors comprising genetic predisposition,
environmental factors and immune (dys-) regulation. In this
context, specific nucleic acids of exogenous or endogenous
origin that signal through nucleic acid-specific Toll-like
receptors (TLRs) have gained much research attention. During
ongoing autoimmune disease microbial nucleic acids contribute
to flares of disease and its aggravation leading to end organ
damage, through unfavourable immune modulation. Apart from
exogenous sources, nucleic acid molecules of endogenous origin
emerge as potential ligands for receptors of host defence,
i.e. TLRs. Rapidly accumulating data on the role of nucleic
acid-specific TLRs has not only provided insights about their
pathogenic potential of endogenous nucleic acid molecules,
but is also fuelling the development of novel immunotherapies.
[Back to top]
Serotonin Involvement in
the Basal Ganglia Pathophysiology: Could the 5-HT2C
Receptor be a New Target for Therapeutic Strategies?
Giuseppe Di Giovanni, Vincenzo Di Matteo, Massimo Pierucci,
Arcangelo Benigno and Ennio Esposito
The basal ganglia are a highly interconnected
group of subcortical nuclei in the vertebrate brain that play
a critical role not only in the control of movements but also
in some cognitive and behavioral functions. Several recent
studies have emphasized that serotonergic pathways in the
central nervous system (CNS) are intimately involved in the
modulation of the basal ganglia and in the pathophysiology
of human involuntary movement disorders. These observations
are supported by anatomical evidence demonstrating large serotonergic
innervation of the basal ganglia. In fact, serotonergic terminals
have been reported to make synaptic contacts with dopamine
(DA)-containing neurons and γ-aminobutyric
acid (GABA)-containing neurons in the striatum, globus pallidus,
subthalamus and substantia nigra. These brain areas contain
the highest concentration of serotonin (5-HT), with the substantia
nigra pars reticulata receiving the greatest input. Furthermore,
in these structures a high expression of 5-HT different receptor
subtypes has been revealed. In this paper, evidence demonstrating
the serotonergic control of basal ganglia functions will be
reviewed, focusing on the role of the 5-HT2C receptor
subtype. In addition, the involvement of 5-HT2C
receptors in neurological disorders such as Parkinson’s
disease and other related motor disorders, and their management
with drugs blocking the 5-HT2C receptor will be
discussed.
[Back to top]
Identifying Accessible Sites
in RNA: The First Step in Designing Antisense Reagents
Wei-Hua Pan and Gary A. Clawson
There is continued interest in development
of antisense reagents (ASRs), including especially antisense
oligonucleotides and small interfering RNAs, for experimental
as well as therapeutic purposes. Optimization of ASRs begins
with target site selection. Here we review protocols which
have been developed to empirically determine effective target
sites in RNAs. Such library selection technologies have demonstrated
clear utility, and in vitro identification of sites
has generally proven effective for cellular applications.
A few groups are developing large combinatorial libraries
and approaches to adapt use of such libraries to individual
target RNAs, as well as learning algorithms to help with the
optimization of target sites, particularly with respect to
small interfering RNAs.
[Back to top]
Targeting Airway Inflammation:
Novel Therapies for the Treatment of Asthma
Garry M. Walsh
It is now widely accepted that airway
inflammation is the key factor underlying the pathogenesis
of asthma. Inhaled corticosteroids remain the most important
anti-inflammatory treatment for asthma. However, they are
rather non-specific in their actions and their use raises
concerns over side effects and compliance issues, particularly
in children and adolescents. Moreover, a significant sub-group
of asthmatic patients responds poorly or not at all to high-dose
inhaled or systemic steroid treatment. Therefore, much effort
is being made to develop novel more specific and safer therapy
for asthma. Significant areas of drug development include
humanised monoclonal antibodies (mAb) for asthma therapy including
those against IL-4, IL-5, TNF and IL-13. Asthma-relevant cytokines
or chemokines have been targeted in a number of other ways.
These include: (1) the use of humanised blocking mAb to their
receptors; (2) removal of cytokines or chemokines via
binding to soluble receptors or small molecule receptor antagonists;
and (3) drugs that block the signal transduction pathways
activated following the interaction of cytokines or chemokines
with their receptors. Another approach is to use anti-inflammatory
cytokines directly or encourage their production thereby suppressing
the allergic inflammatory process; these chemokines include
IL-10, IL-12 and IFN-γ.
Finally, a further promising area involves targeting the allergic
portion of the asthma phenotype using humanised anti-IgE mAb.
This review will discuss the current status, therapeutic potential
and potential problems of these novel drug developments in
asthma therapy.
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