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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 4, 2007
Contents
Endothelial Cell Adhesion Molecules and Cancer Progression
Pp. 377-386
Hanako Kobayashi, Kimberly C. Boelte and P. Charles Lin
[Abstract]
Drug Resistance in Melanoma: New Perspectives
Pp. 387-391
Caterina A.M. La Porta
[Abstract]
Molecular Lipophilicity in Protein Modeling and Drug
Design Pp. 393-415
Roman G. Efremov, Anton O. Chugunov, Timothy V. Pyrkov,
John P. Priestle, Alexander S. Arseniev and Edgar Jacoby
[Abstract]
Challenges and Pitfalls in Antioxidant Research
Pp. 417-430
N. Hermans, P. Cos, L. Maes, T. De Bruyne, D. Vanden Berghe,
A. J. Vlietinck and L. Pieters
[Abstract]
Diversity of Human Immune System Multigene Families
and its Implication in the Genetic Background of Rheumatic
Diseases Pp. 431-439
Naoyuki Tsuchiya, Chieko Kyogoku, Risa Miyashita and Kimiko
Kuroki
[Abstract]
Application Of The EIIP/ISM Bioinformatics Concept
in Development of New Drugs Pp. 441-453
V. Veljkovic, N. Veljkovic, J. A. Esté, A. Hüther
and U. Dietrich
[Abstract]
Selectivity and Affinity Determinants for Ligand Binding
to the Aromatic Amino Acid Hydroxylases Pp. 455-467
Knut Teigen, Jeffrey Alan McKinney, Jan Haavik and Aurora
Martínez
[Abstract]
Balancing the Double-Edged Sword: Metal Ion Homeostasis
and the Ulcer Bug Pp. 469-478
Jeannette M. Whitmire, Hanan Gancz and D. Scott Merrell
[Abstract]
β-Carboline
Alkaloids: Biochemical and Pharmacological Functions
Pp. 479-500
Rihui Cao, Wenlie Peng, Zihou Wang and Anlong Xu
[Abstract]
Abstracts
[Back to top]
Endothelial Cell Adhesion Molecules and Cancer Progression
Hanako Kobayashi, Kimberly C. Boelte and P. Charles Lin
The role of cell adhesion molecules (CAMs), such as intercellular
cell adhesion molecule-1 (ICAM-1), vascular endothelial cell
adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin,
has been studied extensively in the process of inflammation.
These molecules are responsible for recruiting leukocytes
onto the vascular endothelium before extravasation to the
injured tissues. Some circulating cancer cells have been shown
to extravasate to a secondary site using a process similar
to inflammatory cells. The most studied ligands for CAMs expressed
on cancer cells, sialyl Lewis (a/x) antigens, are shown to
be involved in adhesion to endothelial cells by binding to
E-selectin. This process, shared by inflammatory cells and
cancer cells, may partially explain the link between inflammation
and tumorigenesis. Furthermore, this process may elucidate
the therapeutic benefit of anti-inflammatory drugs in cancer
treatment. The complexity of the tumor microenvironment has
been revealed in the past decade. Currently, intense investigation
is aimed at various aspects of the tumor microenvironment
in addition to the tumor cells themselves. Here, we review
the role of CAMs in extravasation of circulating cancer cells,
a key step in metastasis.
[Back to top]
Drug Resistance in Melanoma: New Perspectives
Caterina A.M. La Porta
Melanoma is the most aggressive form of skin cancer and advantages
stages are inevitably resistant to conventional therapeutic
agents. In particular, the inability of undergo apoptosis
in response to chemotherapy and other external stimuli poses
a selective advantage for tumor progression, metastasis formation
as well as resistance to therapy in melanoma.
Herein, we will review the discovery of MDR transporters and
the apoptotic mechanisms used by melanoma cells. Furthermore,
the novel strategies to overcome tumor chemoresistance will
also discuss. In particular, we will review the cancer stem
cell hypothesis and how the failure of MDR reversal agents
might increase the therapeutic index of substrate antineoplastic
agents.
[Back to top]
Molecular Lipophilicity in Protein Modeling and Drug
Design
Roman G. Efremov, Anton O. Chugunov, Timothy V. Pyrkov,
John P. Priestle, Alexander S. Arseniev and Edgar Jacoby
Hydrophobic interactions play a key role in the folding and
maintenance of the 3-dimensional structure of proteins, as
well as in the binding of ligands (e.g. drugs) to protein
targets. Therefore, quantitative assessment of spatial hydrophobic
(lipophilic) properties of these molecules is indispensable
for the development of efficient computational methods in
drug design. One possible solution to the problem lies in
application of a concept of the 3-dimensional molecular hydrophobicity
potential (MHP). The formalism of MHP utilizes a set of atomic
physicochemical parameters evaluated from octanol-water partition
coefficients (log P) of numerous chemical compounds.
It permits detailed assessment of the hydrophobic and/or hydrophilic
properties of various parts of molecules and may be useful
in analysis of protein-protein and protein-ligand interactions.
This review surveys recent applications of MHP–based
techniques to a number of biologically relevant tasks. Among
them are: (i) Detailed assessment of hydrophobic/hydrophilic
organization of proteins; (ii) Application of this data to
the modeling of structure, dynamics, and function of globular
and membrane proteins, membrane-active peptides, etc.
(iii) Employment of the MHP-based criteria in docking simulations
for ligands binding to receptors.
It is demonstrated that the application of the MHP-based techniques
in combination with other molecular modeling tools (e.g. Monte
Carlo and molecular dynamics simulations, docking, etc.) permits
significant improvement to the standard computational approaches,
provides additional important insights into the intimate molecular
mechanisms driving protein assembling in water and in biological
membranes, and helps in the computer-aided drug discovery
process.
[Back to top]
Challenges and Pitfalls in Antioxidant Research
N. Hermans, P. Cos, L. Maes, T. De Bruyne, D. Vanden Berghe,
A. J. Vlietinck and L. Pieters
Over the last decade, much research has focused on the potential
health benefits of antioxidants and indeed many synthetic
and natural compounds have been evaluated for their antioxidant
profile. However, in several studies only a limited number
of assays, often poorly validated, are used and the techniques
available frequently lack specificity. These limitations may
incorrectly influence the results. This review will therefore
focus on several pitfalls that may emerge in vitro
and in vivo antioxidant research. First, different
in vitro techniques to determine antioxidant potential
are discussed, including radical scavenging assays and fingerprinting
methods. As a rule, a panel of different assays is indispensable
to characterize and establish in vitro antioxidant
activity. Furthermore, as problems of absorption, distribution,
metabolism and excretion are only accounted for by in
vivo studies, the need for in vivo antioxidant
research is pointed out. Several methods to characterize the
in vivo activity of antioxidants, including major
drawbacks and pitfalls of some assays, have been discussed.
The availability of both a representative “oxidative
stress” animal model and a battery of well-validated
assays to assess the broad diversity of oxidative damage and
antioxidative defence parameters, are crucial for antioxidant
research in vivo.
[Back to top]
Diversity of Human Immune System Multigene Families
and its Implication in the Genetic Background of Rheumatic
Diseases
Naoyuki Tsuchiya, Chieko Kyogoku, Risa Miyashita and Kimiko
Kuroki
A large number of molecules in the immune system are encoded
by multigene families. These genes are rich in pairs of activating
and inhibitory receptors that share the same ligands, thereby
playing a crucial role in immunoregulation. Furthermore, multigene
families tend to be highly polymorphic. Thus, multigene families
are strong candidates for containing genes that enhance susceptibility
to immune system-related diseases. Here, we review studies
from our group, as well as other investigators, on three multigene
families that belong to the immunoglobulin (Ig) - like receptor
superfamily: Fcγ
receptor (FCGR), killer cell Ig-like receptor (KIR)
and leukocyte Ig-like receptor (LILR) families.
FCGR genes have been implicated in susceptibility
to systemic lupus erythematosus (SLE). In FCGR2B
encoding an inhibitory receptor expressed in B cells, monocytes
and dendritic cells, a polymorphism within the transmembrane
region, Ile232Thr, was identified and found to be associated
with susceptibility to SLE in three Asian populations. Functional
analyses revealed that SLE-associated FcγRIIb-232Thr
was less efficient in entering the membrane lipid raft, and
exhibited reduced inhibitory potential against B cell receptor
signaling. Although the frequency of this polymorphism was
low in Caucasians, another polymorphism within the promoter
region was reported to be associated with SLE. KIR/HLA
combinations have been shown to be associated with various
autoimmune and infectious diseases. Recently, LILR
families have also been found to be highly polymorphic, and
association with several diseases has been identified. These
results emphasize the role of multigene families in the diversity
of human immune response and susceptibility to diseases.
[Back to top]
Application Of The EIIP/ISM Bioinformatics Concept
in Development of New Drugs
V. Veljkovic, N. Veljkovic, J. A. Esté, A. Hüther
and U. Dietrich
The development of a new therapeutic drug is a complex, lengthy
and expensive process. On average, only one out of 10,000
– 30,000 originally synthesized compounds will clear
all the hurdles on the way to becoming a commercially available
drug. The process of early and full preclinical discovery
and clinical development for a new drug can take twelve to
fifteen years to complete, and cost approximately 800 million
dollars. The field of bioinformatics has become a major part
of the drug discovery pipeline playing a key role in improvement
and acceleration of this time and money consuming process.
Here we reviewed the application of the EIIP/ISM bioinformatics
concept for the development of new drugs. This approach, connecting
the electronion interaction potential of organic molecules
and their biological properties, can significantly reduce
development time through (i) identification of promising lead
compounds that have some activity against a disease by fast
virtual screening of the large molecular libraries, (ii) refinement
of selected lead compounds in order to increase their biological
activity, and (iii) identification of domains of proteins
and nucleotide sequences representing potential targets for
therapy. Special attention is paid in this review to the application
of the EIIP/ISM bioinformatics platform along with other experimental
techniques (screening of a phage displayed peptide libraries,
testing selected peptides and small molecules for antiviral
activity in vitro) in development of HIV entry inhibitors,
representing a new generation of the AIDS drugs.
[Back to top]
Selectivity and Affinity Determinants for Ligand Binding
to the Aromatic Amino Acid Hydroxylases
Knut Teigen, Jeffrey Alan McKinney, Jan Haavik and Aurora
Martínez
Hydroxylation of the aromatic amino acids phenylalanine, tyrosine
and tryptophan is carried out by a family of non-heme iron
and tetrahydrobiopterin (BH4) dependent enzymes, i.e. the
aromatic amino acid hydroxylases (AAHs). The reactions catalyzed
by these enzymes are important for biomedicine and their mutant
forms in humans are associated with phenylketonuria (phenylalanine
hydroxylase), Parkinson’s disease and DOPA-responsive
dystonia (tyrosine hydroxylase), and possibly neuropsychiatric
and gastrointestinal disorders (tryptophan hydroxylase 1 and
2). We attempt to rationalize current knowledge about substrate
and inhibitor specificity based on the three-dimensional structures
of the enzymes and their complexes with substrates, cofactors
and inhibitors. In addition, further insights on the selectivity
and affinity determinants for ligand binding in the AAHs were
obtained from molecular interaction field (MIF) analysis.
We applied this computational structural approach to a rational
analysis of structural differences at the active sites of
the enzymes, a strategy that can help in the design of novel
selective ligands for each AAH.
[Back to top]
Balancing the Double-Edged Sword: Metal Ion Homeostasis
and the Ulcer Bug
Jeannette M. Whitmire, Hanan Gancz and D. Scott Merrell
The essential nature of many metals is counterbalanced by
the toxic effect that they can exert on both the eukaryotic
and prokaryotic cell when not properly controlled. As such,
virtually all organisms have developed regulatory systems
that are required to maintain metal ion homeostasis. Helicobacter
pylori is arguably the most successful bacterial pathogen
in the world; the bacterium colonizes more than 50% of the
world’s population. H. pylori lives in the
acidic environment of the stomach and causes a persistent
infection that results in disease sequelae such as gastritis,
iron-deficiency anemia, ulcer disease and gastric cancer.
A requirement of colonization is that the bacterium successfully
competes with host cells for available metal ions. As such,
it is perhaps no surprise that several crucial colonization
factors utilize metal as an essential cofactor. Recent investigations
into the absolute requirement for different metal ions and
the need to manage their use have shown that metal ion homeostasis
is achieved by H. pylori through the utilization
of an intricate regulatory cascade that ensures metal uptake
without toxic side effects. Herein we discuss this cascade,
the role that individual metal ions play in H. pylori
colonization and disease and the possibility that these metal
homeostasis cascade components may serve as good targets for
rational drug design to eradicate H. pylori infection.
[Back to top]
β-Carboline
Alkaloids: Biochemical and Pharmacological Functions
Rihui Cao, Wenlie Peng, Zihou Wang and Anlong Xu
β-Carboline
alkaloids are a large group of natural and synthetic indole
alkaloids with different degrees of aromaticity, some of which
are widely distributed in nature, including various plants,
foodstuffs, marine creatures, insects, mammalians as well
as human tissues and body fluids. These compounds are of great
interest due to their diverse biological activities. Particularly,
these compounds have been shown to intercalate into DNA, to
inhibit CDK, Topisomerase, and monoamine oxidase, and to interact
with benzodiazepine receptors and 5-hydroxy serotonin receptors.
Furthermore, these chemicals also demonstrated a broad spectrum
of pharmacological properties including sedative, anxiolytic,
hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic
as well as antimicrobial activities. In this review, we summerized
the biochemical and pharmacological functions of β-carboline
alkaloids.
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