| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 8, 2010
Contents
Targeting Tumor Lymphangiogenesis: An Update Pp.
698-708
M. Raica and D. Ribatti
[Abstract] [Purchase
Article]
[PMID:
20088760 PubMed - indexed for MEDLINE]
Molecular Bases of Liver Cancer Refractoriness to Pharmacological
Treatment Pp. 709-740
J.J.G. Marin, M.R. Romero and O. Briz
[Abstract] [Purchase
Article]
[PMID:
20088759 PubMed - indexed for MEDLINE]
The GP120 Molecule of HIV-1 and its Interaction with T Cells
Pp. 741-749
V. Yoon, M. Fridkis-Hareli, S. Munisamy, J. Lee,
D. Anastasiades and L. Stevceva
[Abstract] [Purchase
Article] [PMID:
20088758 PubMed - indexed for MEDLINE]
TSG101: A Novel Anti-HIV-1 Drug Target Pp.
750-758
Hongfei Chen, Xinyong Liu, Zhenyu Li, Peng Zhan
and Erik De Clercq
[Abstract] [Purchase
Article] [PMID:
20088757 PubMed - indexed for MEDLINE]
Editor’s
Choice
Induced Pluripotent Stem Cells as a Model for Accelerated
Patient- and Disease-specific Drug Discovery Pp.
759-766
I. Gunaseeli, M.X. Doss, C. Antzelevitch, J. Hescheler
and A. Sachinidis
[Abstract] [Purchase
Article]
[PMID:
20088756 PubMed - indexed for MEDLINE]
Towards Accurate Free Energy Calculations in Ligand
Protein-Binding Studies Pp. 767-785
Thomas Steinbrecher and Andreas Labahn
[Abstract] [Purchase
Article]
[PMID:
20088755 PubMed - indexed for MEDLINE]
The Structure and Functions of P-Glycoprotein
Pp. 786-800
Y. Li, H. Yuan, K. Yang, W. Xu, W. Tang and X.
Li
[Abstract] [Purchase
Article]
[PMID:
20088754 PubMed - indexed for MEDLINE]
Abstracts
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Article] [PMID:
20088760 PubMed - indexed for MEDLINE]
Targeting Tumor Lymphangiogenesis: An Update
M. Raica and D. Ribatti
Various human tumors preferentially metastasize by lymphatic
route and lymphovascular invasion predicts lymph node metastasis.
In this review article, we will summarize recent literature
data concerning lymphangiogenesis, focusing on tumor lymphangiogenesis.
In detail, we try to answer some important questions related
to: a) The specificity of lymphatic endothelial cell markers;
b) The differential characteristics of lymphatic vessels in
tumors; c) The interplay between different lymphangiogenic
factors; d) The role of pre-existing and newly-formed lymphatic
vessels in tumors and their proliferative potential; e) The
role of lymphatic vessels in tumor metastases; e) The prognostic
significance of lymphatic microvascular density in tumors;
f) The inhibition of lymphangiogenesis in tumors.
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[Purchase
Article] [PMID:
20088759 PubMed - indexed for MEDLINE]
Molecular Bases of Liver Cancer Refractoriness to Pharmacological
Treatment
J.J.G. Marin, M.R. Romero and O. Briz
Hepatocellular carcinoma and cholangiocarcinoma are the two
most important primary malignancies of the liver. These are
among the tumours with the lowest response to pharmacological
treatment based on currently available drugs. This is due
either to the existence of refractoriness of the initial tumour
or to the ability of cancer cells to develop chemoresistance
during treatment. Liver cancers share some of the mechanisms
responsible for drug refractoriness with other types of tumours,
such as a reduction in drug uptake; enhanced drug export;
intracellular inactivation of the active agent; alteration
of the molecular target; an increase in the activity of the
target route to be inhibited, or the appearance or stimulation
of alternative routes; enhanced repair of drug-induced modifications
in the target molecules, and the activation/inhibition of
intracellular signalling pathways, all of which lead to a
negative balance between the apoptosis/survival of tumour
cells. The aim of the present article is to review how these
mechanisms of chemoresistance affect the different families
of drugs that are being or have been used to treat hepatocellular
carcinoma and cholangiocarcinoma. A better understanding of
the molecular bases of drug refractoriness is needed in order
to develop novel drugs or pharmacological strategies aimed
at overcoming resistance to anticancer agents.
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[Purchase
Article] [PMID:
20088758 PubMed - indexed for MEDLINE]
The GP120 Molecule of HIV-1 and its Interaction with T Cells
V. Yoon, M. Fridkis-Hareli, S. Munisamy, J. Lee,
D. Anastasiades and L. Stevceva
The gp120 molecule of HIV-1 is a glycoprotein that is part
of the outer layer of the virus. It presents itself as viral
membrane spikes consisting of 3 molecules of gp120 linked
together and anchored to the membrane by gp41 protein. Gp120
is essential for viral infection as it facilitates HIV entry
into the host cell and this is its best-known and most researched
role in HIV infection. However, it is becoming increasingly
evident that gp120 might also be facilitating viral persistence
and continuing HIV infection by influencing the T cell immune
response to the virus. Several mechanisms might be involved
in this process of which gp120 binding to the CD4 receptor
of T cells is the best known and most important interaction
as it facilitates viral entry into the CD4+ cells and their
depletion, a hallmark of the HIV infection. Gp120 is shed
from the viral membrane and accumulates in lymphoid tissues
in significant amounts. Here, it can induce apoptosis and
severely alter the immune response to the virus by dampening
the antiviral CTL response thus impeding the clearance of
HIV. The effects of gp120 and how it interacts and influences
T cell immune response to the virus is an important topic
and this review aims to summarize what has been published
so far in hopes of providing guidance for future work in this
area.
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20088757 PubMed - indexed for MEDLINE]
TSG101: A Novel Anti-HIV-1 Drug Target
Hongfei Chen, Xinyong Liu, Zhenyu Li, Peng Zhan
and Erik De Clercq
The life cycle of HIV-1 requires extensive assistance from
the host cell proteins and pathways. TSG101 is one of the
cellular proteins involved in the budding process of HIV-1,
and plays an important role in the cellular vacuolar protein
sorting (Vps) pathway. Its main function being recognizing
ubiquitinated cargo, TSG101 also proved to be essential for
the budding process of HIV-1 virions. In this process, TSG101
is recruited from internal site of the infected cell to the
budding site to aid in the release of the HIV-1 virus particles.
Depletion of TSG101 from virus-producing cells can lead to
a budding defect. Therefore, TSG101 is a potentially new attractive
target for therapeutic intervention in AIDS. This review describes
the structure and function of TSG101 and latest progress in
the discovery of TSG101-directed HIV-1 inhibitors.
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[PMID:
20088756 PubMed - indexed for MEDLINE]
Induced Pluripotent Stem Cells as a Model for Accelerated
Patient- and Disease-specific Drug Discovery
I. Gunaseeli, M.X. Doss, C. Antzelevitch, J. Hescheler
and A. Sachinidis
Human induced pluripotent stem (iPS) cells hold great promise
for therapy of a number of degenerative diseases such as ischemic
heart failure, Parkinson’s disease, Alzheimer’s
disease, diabetes mellitus, sickle cell anemia and Huntington
disease. They also have the potential to accelerate drug discovery
in 3 ways. The first involves the delineation of chemical
components for efficient reprogramming of patient’s
blood cells or cells from biopsies, obviating the need for
cellular delivery of reprogramming exogenous transgenes, thereby
converting hope into reality for patients suffering from degenerative
diseases. Patients worldwide stand to benefit from the clinical
applicability of iPS cell-based cell replacement therapy for
a number of degenerative diseases. The second is the potential
for discovering novel drugs in a high throughput manner using
patient-specific iPS cell-derived somatic cells possessing
the etiology of the specific disease. The third is their suitability
for toxicological testing of drugs and environmental factors.
This review focuses on these potential applications of iPS
cells with special emphasis on recent updates of iPS cell
research contributing to the accelerated drug discovery.
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[PMID:
20088755 PubMed - indexed for MEDLINE]
Towards Accurate Free Energy Calculations in Ligand
Protein-Binding Studies
Thomas Steinbrecher and Andreas Labahn
Cells contain a multitude of different chemical reaction paths
running simultaneously and quite independently next to each
other. This amaz¬ing feat is enabled by molecular recognition,
the ability of biomolecules to form stable and specific complexes
with each other and with their substrates. A better understanding
of this process, i.e. of the kinetics, structures and thermodynamic
properties of biomolecule binding, would be invaluable in
the study of biological systems. In addition, as the mode
of action of many pharmaceuticals is based upon their inhibition
or activation of biomolecule targets, predictive models of
small molecule receptor binding are very helpful tools in
rational drug design. Since the goal here is normally to design
a new compound with a high inhibition strength, one of the
most important thermodynamic properties is the binding free
energy ΔG0.
The prediction of binding constants has always been one of
the major goals in the field of computational chemistry, because
the ability to reliably assess a hypothetical compound's binding
properties without having to synthesize it first would save
a tremendous amount of work. The different approaches to this
question range from fast and simple empirical descriptor methods
to elaborate simulation protocols aimed at putting the computation
of free energies onto a solid foundation of statistical thermodynamics.
While the later methods are still not suited for the screenings
of thousands of compounds that are routinely performed in
computational drug design studies, they are increasingly put
to use for the detailed study of protein ligand interactions.
This review will focus on molecular mechanics force field
based free energy calculations and their application to the
study of protein ligand interactions. After a brief overview
of other popular methods for the calculation of free energies,
we will describe recent advances in methodology and a variety
of exemplary studies of molecular dynamics simulation based
free energy calculations.
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[Purchase
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[PMID:
20088754 PubMed - indexed for MEDLINE]
The Structure and Functions of P-Glycoprotein
Y. Li, H. Yuan, K. Yang, W. Xu, W. Tang and X.
Li
P-glycoprotein (P-gp) is an ATP-driven transmembrane transporter
capable of effluxing a wide variety of structurally diverse
and functionally unrelated hydrophobic compounds out of the
cell. Multidrug resistance (MDR), often associated with the
over-expression of P-gp, has been implicated as a major obstacle
to effective chemotherapy for cancer, parasitic diseases,
AIDS, and other diseases. Drug efflux mediated by P-gp is
also involved in decreasing the oral bioavailability of drugs
by limiting intestinal absorption. Our appreciation of the
structural and functional aspects of P-gp has definitely improved
in recent years, benefiting from the deciphering of the structure
of some bacterial transporters that paved the way for construction
of homology models for more complex transporters. Here, we
will review the recent advances in the studies of the structure
and functional characteristics of P-gp with the hopes of facilitating
rational drug design in developing novel potent MDR modulators.
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