|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 2, 2008
Contents
Theoretical and Practical Considerations in Virtual Screening:
A Beaten Field? Pp. 107-116
Maria Kontoyianni, Prakash Madhav, Eric Suchanek and William
Seibel
[Abstract]
Current and Emerging Therapeutic Approaches in HCV
Related Mixed Cryoglobulinemia Pp. 117-126
D. Sansonno, F.A. Tucci, L. Troiani, L. Sansonno and F.
Dammacco
[Abstract]
Strategies for Novel Therapeutic Approaches Targeting
Cytokines and Signaling Pathways of Osteoclasto- and Osteoblastogenesis
in the Fight Against Immune Mediated Bone and Joint Diseases
Pp. 127-136
W. Sipos, P. Pietschmann and M. Rauner
[Abstract]
Inhibitors of 17β-Hydroxysteroid
Dehydrogenase Type Pp.137- 150
P. Brožic, T. Lanišnik Rižner and S. Gobec
[Abstract]
Schwann Cell Transplantation for CNS Repair Pp. 151-160
A.A. Lavdas, F. Papastefanaki, D. Thomaidou and R. Matsas
[Abstract]
The Fight Against Drug-Resistant Malaria: Novel Plasmodial
Targets and Antimalarial Drugs Pp. 161-171
Seoung-Ryoung Choi, Prasenjit Mukherjee and Mitchell A.
Avery
[Abstract]
Role of Oxidative Stress in the Development of Vascular Injury
and its Therapeutic Intervention by Nifedipine Pp.
172-177
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori Matsui
[Abstract]
Recent Updates on the Calcium-Sensing Receptor
as a Drug Target Pp. 178-186
Ritu Trivedi, Ambrish Mithal and Naibedya Chattopadhyay
[Abstract]
Innovative Strategies in In Vivo Apoptosis Imaging
Pp. 187-194
Johann Schoenberger, Johann Bauer, Jutta Moosbauer, Christoph
Eilles and Daniela Grimm
[Abstract]
Design, Structure Activity Relationships and X-Ray
Co Crystallography of Non-Steroidal LXR Agonists
Pp. 195-209
D.J. Bennett, E.L. Carswell, A.J. Cooke, A.S. Edwards
and O. Nimz
[Abstract]
Abstracts
[Back to top]
Theoretical and Practical Considerations
in Virtual Screening: A Beaten Field?
Maria Kontoyianni, Prakash Madhav, Eric Suchanek and William
Seibel
In this review, several aspects of virtual screening
are presented. Although, docking and scoring have been the
most widely employed techniques, ligand-based virtual screening
has also gained momentum in recent years. We have classified
the docking programs into four categories, based on their
underline theories, and accordingly describe the most up-to-date
algorithms and newest versions. Similarly, three categories
of scoring functions are presented, while their weighting
schemes on particular binding terms are discussed. The latter
is important, since knowledge of the function can be used
to select the ones that could be more appropriate for targets
of similar nature. Challenging aspects, such as protein flexibility
and practices to select the most appropriate docking/scoring
schemes, are also discussed. Finally, a real-life example
is presented where a pharmacophore-driven approach combined
with a docking exercise were undertaken in an iterative manner
to successfully enhance the virtual screening hit rates. In
the end, we present our own perspective for best practices
in the field based on our experiences.
[Back to top]
Current and Emerging Therapeutic Approaches in HCV Related
Mixed Cryoglobulinemia
D. Sansonno, F.A. Tucci, L. Troiani, L. Sansonno and F.
Dammacco
Recognition of hepatitis C virus (HCV) as an etiological
factor in mixed cryoglobulinemia (MC) has dramatically changed
our point of view in its treatment. Emphasis is placed on
abatement and clearance of viral load and deletion of clonal
expansions of IgM molecules with rheumatoid factor activity-synthesising
B cells. The purpose of this review is to discuss the underlying
scientific rationale and results of clinical studies of new
treatment approaches to MC, with a focus on cell-depleting
therapies and chemokine blockade. Additional antiviral agents
directed to several phases of HCV life cycle acting with different
or alternate mechanisms are proposed with the goal to enhance
response rates more broadly suitable for MC patients with
vasculitis and peripheral neuropathies. The majority of the
available data on these new treatment approaches stems from
open-label studies, but controlled trials are under way. Therapy
directed against chemokines and/or cytokines represents an
interesting and promising future target.
[Back to top]
Strategies for Novel Therapeutic Approaches Targeting
Cytokines and Signaling Pathways of Osteoclasto- and Osteoblastogenesis
in the Fight Against Immune Mediated Bone and Joint Diseases
W. Sipos, P. Pietschmann and M. Rauner
For many bone and joint diseases in humans, including
postmenopausal osteoporosis, rheumatoid arthritis, and ankylosing
spondylitis, an immune-mediated etiology has either been proven
or is considered as a co-factor in pathogenesis. The identification
of the receptor activator of nuclear factor κB
(RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG)-interplay
and the in-depth characterization of the signaling pathways
induced upon RANK activation, including molecules such as
TNF receptor-associated factor 6 (TRAF6), nuclear factor-κB
(NF-κB),
and signal transducer and activator of T cells (STAT)-3, now
promise to give the opportunity to target osteoclastogenesis
specifically. Additionally, many byways influencing osteoclastogenesis
have been elucidated, thus giving rise to additional therapeutic
approaches. These are based mainly upon the effects of diverse
cytokines on osteoclast differentiation with interleukin (IL)-17
and interferone (IFN)-γ
being most prominent at the moment. The same applies for the
recently established signaling pathways in osteoblastogenesis,
which have attracted much attention in the recent years. In
this respect, much attention has been attributed towards bone
morphogenetic proteins (BMPs) and the Wnt signaling cascade.
In this review, an overview on the key molecules, which (could)
serve as promising targets for novel therapeutic interventions
with the aim of enhancing osteoblast formation or suppressing
osteoclast development, is given. Further on, antibody-based
therapeutical schemes as well as methodologically novel, albeit
predominantly theoretical at the moment, strategies in the
fight against immune-mediated osteopathologies are discussed.
[Back to top]
Inhibitors of 17β-Hydroxysteroid
Dehydrogenase Type
P. Brožic, T. Lanišnik Rižner and S. Gobec
Carcinogenesis of hormone-related cancers involves hormone-stimulated
cell proliferation, which increases the number of cell divisions
and the opportunity for random genetic errors. In target tissues,
steroid hormones are interconverted between their potent,
high affinity forms for their respective receptors and their
inactive, low affinity forms. One group of enzymes responsible
for these interconversions are the hydroxysteroid dehydrogenases,
which regulate ligand access to steroid receptors and thus
act at a pre-receptor level. As part of this group, the 17β-hydroxysteroid
dehydrogenases catalyze either oxidation of hydroxyl groups
or reduction of keto groups at steroid position C17. The thoroughly
characterized 17β-hydroxysteroid
dehydrogenase type 1 activates the less active estrone to
estradiol, a potent ligand for estrogen receptors. This isoform
is expressed in gonads, where it affects circulating levels
of estradiol, and in peripheral tissue, where it regulates
ligand occupancy of estrogen receptors. Inhibitors of 17β-hydroxysteroid
dehydrogenase type 1 are thus highly interesting potential
therapeutic agents for the control of estrogen-dependent diseases
such as endometriosis, as well as breast and ovarian cancers.
Here, we present the review on the recent development of inhibitors
of 17β-hydroxysteroid
dehydrogenase type 1 published and patented since the previous
review of 17β-hydroxysteroid
dehydrogenase inhibitors of Poirier (Curr. Med. Chem., 2003,
10, 453). These inhibitors are divided into two separate
groups according to their chemical structures: steroidal and
non-steroidal 17β-hydroxysteroid
dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative
activities and selectivities over other 17β-hydroxysteroid
dehydrogenases that are involved in local regulation of estrogen
action (types 2, 7 and 12) are also presented.
[Back to top]
Schwann Cell Transplantation for CNS Repair
A.A. Lavdas, F. Papastefanaki, D. Thomaidou and R. Matsas
Demyelination occurs in several central nervous system
(CNS) disorders, including multiple sclerosis, viral infection
and spinal cord injury and can result in severe functional
impairment. Therefore there is great interest in developing
therapies promoting repair in CNS demyelinating diseases and
trauma. Cell replacement therapy is an attractive approach
for myelin repair, and experimental transplantation has provided
convincing evidence of the repair potential of grafted myelin-forming
cells. Schwann cells (SCs), oligodendrocyte progenitors, olfactory
ensheathing cells and embryonic and neural stem cells have
been shown to form myelin after transplantation into the demyelinated
CNS. SCs are among the most promising candidates for autologous
grafting. They can remyelinate spinal cord lesions after experimental
demyelination, leading in some cases to functional recovery
in rodent and primate models. However, SCs do not normally
enter the CNS, and migration of SCs transplanted in CNS white
matter is inhibited by astrocytes. As SC migration and myelination
is mediated by interactions of sets of extracellular matrix
molecules with cell surface molecules, genetic engineering
of SCs to alter aspects of these interactions is a possible
way forward. Thus efforts towards the development of SC-based
therapies are focused in enhancing their migration and functional
integration into the lesioned CNS. In addition, efforts are
being made to use these cells as gene delivery vehicles for
an array of molecules with repair potential. In this review
we summarize data from the recent literature regarding the
use of SCs in CNS repair and discuss the prospects for future
therapeutic applications.
[Back to top]
The Fight Against Drug-Resistant Malaria: Novel Plasmodial
Targets and Antimalarial Drugs
Seoung-Ryoung Choi, Prasenjit Mukherjee and Mitchell A.
Avery
Malaria, one of the major reemerging parasitic diseases,
is caused by protozoal parasites belonging to the genus plasmodia.
Antimalarial drugs have played a mainstream role in controlling
the spread of malaria through the treatment of patients infected
with the plasmodial parasites and controlling its transmissibility.
The current line of therapy against malaria is faced with
the hurdles of a low or total lack of efficacy due to the
evolution of drug-resistant strains of the malarial parasites.
Preventive vaccination against malaria is an ideal solution
to this problem but is not expected to arrive for at least
a decade. Development of antimalarial drugs involving novel
mechanisms of action is therefore of imminent importance.
Several novel drug candidates of synthetic and natural products
origin as well as their combination therapies are currently
being evaluated for their efficacy against the drug-resistant
strains of the parasites. Various plasmodial targets/pathways,
such as the Purine salvage pathway, Pyrimidine biosynthesis
pathway as well as the processes in the apicoplast, have been
identified and are being utilized for the discovery and development
of novel antimalarial therapies. This review provides an overview
of the latest developments in terms of drugs, combination
therapies and novel plasmodial targets being carried out to
counter the menace of drug-resistant malaria.
[Back to top]
Role of Oxidative Stress in the Development of Vascular
Injury and its Therapeutic Intervention by Nifedipine
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori Matsui
Dihydropyridine-based calcium antagonists (DHPs) are
widely used drugs for the treatment of hypertension and angina
pecto-ris. We, along with others, have recently found that
nifedipine, one of the most widely used DHPs, inhibits apoptotic
cell death of endothelial cells (ECs) as well as vascular
inflammation and subsequently improves endothelial function
in patients with cardiovascular risk factors, including hypertension
and/or diabetes, thus slowing the development and progression
of atherosclerosis in these patients. Several papers have
suggested that nifedipine exerts beneficial metabolic effects
in vivo through its anti-inflammatory properties
as well. However, the underlying molecular mechanisms for
the cardiometabolic actions of nifedipine remain to be elucidated,
because ECs do not possess voltage-operated L-type calcium
channels. Meanwhile, we have very recently found that Bay
w 9798, a dihydropyridine structurally related to nifedipine
with no calcium antagonistic ability, has anti-oxidative and
anti-inflammatory properties in vitro. In this paper,
we review the role of oxidative stress in the development
of vascular injury, especially focusing on the relationships
between advanced glycation end products-receptor system, oxidized
low-density lipoprotein and tumor necrosis factor-α
and vasculopathy. We further discuss the potential
clinical utility of anti-oxidative properties of nifedipine
on various cardiometabolic disorders.
[Back to top]
Recent Updates on the Calcium-Sensing Receptor as
a Drug Target
Ritu Trivedi, Ambrish Mithal and Naibedya Chattopadhyay
Parathyroid hormone (PTH) secreted from parathyroid cells
is a key regulator of circulating levels of calcium ion, which
is maintained within a narrow physiological range mainly by
the action of a cell surface Ca2+ -sensing
receptor (CaSR) residing on parathyroid cells. The CaSR belongs
to the family C of G-protein-coupled receptors (GPCRs), all
members of which have a large extra cellular domain called
Venus flytrap, akin to bacterial nutrient sensor. Promiscuity
of the CaSR is reflected in its binding to several physiologically
relevant di- or polyvalent cations that could elicit cellular
signaling, yet the ligand specificity remains poor. This problem
has been circumvented by the discovery of calcimimetics, the
positive allosteric modulators of the CaSR that activate the
CaSR on parathyroid cells, immediately suppressing PTH secretion.
Out of several small molecules that act as calcimimetics,
cinacalcet is the most extensively studied. The discovery
of the CaSR and these specific agonists provides important
insights into the discovery of new drugs that will be discussed
in this review from the perspective of their structure-activity
relationship. The calcimimetic compound cinacalcet has obtained
regulatory approval for the treatment of hyperparathyroidism
and is the first positive allosteric modulator of any GPCR
to reach the market. It has other important uses in dialysis
patients with end-stage renal disease, in whom it decreases
Ca ×
P product. Pharmaceutically converse to calcimimetics are
calcilytic compounds, which antagonize parathyroid CaSR and
stimulate PTH secretion. Antagonism of the CaSR has the potential
to yield an anabolic therapy for osteoporosis that awaits
clinical validation.
[Back to top]
Innovative Strategies in In Vivo Apoptosis
Imaging
Johann Schoenberger, Johann Bauer, Jutta Moosbauer, Christoph
Eilles and Daniela Grimm
Apoptosis (programmed cell death) plays a key role in the
pathogenesis of many disorders including cerebral and myocardial
ischemia, autoimmune and neurodegenerative diseases, infections,
organ and bone marrow transplant rejection, and tumor response
to chemotherapy and/or radiotherapy. Apoptosis in itself represents
a complex mechanism where numerous (pro-apoptotic and anti-apoptotic)
molecules interact in an elaborate manner.
Since the original description by Kerr et al. in
1972, clinical assessment of apoptosis has always required
biopsies or aspirated material for in vitro investigations.
Several well-established methods are available for in
vitro tests using tissue specimens. However, a non-invasive
detection of apoptosis would be of great benefit for many
patients in various situations. Today, non-invasive techniques
for direct in vivo detection of apoptotic cells are
rare and urgently need improvement. The early in vivo
detection of apoptotic cells can provide the physician with
important information to develop further therapeutic strategies
in chemotherapy or radiotherapy of tumors, in transplantation
of organs, or in healing of infarct areas.
In some preliminary publications, several authors reported
on the in vivo use of caspase-inhibitors and annexin
V, labeled with indium-111, technetium-99m, iodine-123, iodine-124
or fluoride-18. In the present paper, we review the current
applicability of both techniques for in vivo apoptosis
imaging, and discuss the methodical problems.
[Back to top]
Design, Structure Activity Relationships and X-Ray
Co Crystallography of Non-Steroidal LXR Agonists
D.J. Bennett, E.L. Carswell, A.J. Cooke, A.S. Edwards
and O. Nimz
The Liver X Receptor (LXR) α
and β
isoforms are members of the type II nuclear receptor family
which function as a hetero-dimer with the Retinoid X Receptor
(RXR). Upon agonist binding, the formation of the LXR/RXR
heterodimer takes place and ultimately the regulation of a
number of genes begins. The LXR isoforms share 77% sequence
homology, with LXRα
having highest expression in liver, intestine, adipose tissue,
and macrophages and LXRβ
being ubiquitously expressed.
The aim of this article is to review the reported medicinal
chemistry strategies towards the optimisation of novel non-steroidal
chemotypes as LXR agonists. An analysis of the structural
features important for LXR ligand binding will be given, utilising
both structural activity relationship data obtained from LXR
assays as well as X-ray co-crystallographic data obtained
with LXR ligands and the LXR ligand binding domain (LBD).
The X-ray co-crystallographic data analysis will detail the
key structural interactions required for LXR binding/agonist
activity and reveal the differences observed between chemotype
classes.
It has been postulated that a LXRβ
selective compound may have a beneficial outcome on the lipid
profile for a ligand by dissociating the favourable and unfavourable
effects of LXR agonists. Whilst there have been a few examples
of compounds showing a modest level of LXRα
selectivity, obtaining a potent LXRβ
selective compound has been more challenging. Analysis of
the SAR and X-ray co-crystallographic data suggests that the
rational design of a LXRβ
selective compound will not be trivial.
|
