| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 11, Number 3, 2005
Contents
Computer Aided Drug Design
Executive Editor: M. Rami Reddy
Editorial
M. Rami Reddy
[Editorial
In PDFs]
Computer Aided Drug Design Strategies Used in
the Discovery of Fructose 1, 6-Bisphosphatase Inhibitors Pp.283-294
M. Rami Reddy and Mark D. Erion
[Abstract]
[Full text article]
Recent Developments in the Design of Specific
Matrix Metalloproteinase Inhibitors aided by Structural and
Computational Studies Pp.295-322
B. Govinda Rao
[Abstract] [Full
text article]
Docking: Successes and Challenges Pp.323-333
Venkatraman Mohan, Alan C. Gibbs, Maxwell D. Cummings,
Edward P. Jaeger and Renee L. DesJarlais
[Abstract] [Full
text article]
Discovery Strategies in a BioPharmaceutical Startup:
Maximising your Chances of Success Using Computational Filters
Pp.335-344
A. Jennings and M. Tennant
[Abstract] [Full
text article]
Computer-Based Strategy for Modeling the Interaction
of AGRP and Related Peptide Ligands with the AGRP-Binding
Site of Murine Melanocortin Receptors Pp.345-356
Xiang Wang and Nigel G.J. Richards
[Abstract] [Full
text article]
Antiangiogenic Agents: Studies on Fumagillin and
Curcumin Analogs Pp.357-373
M.S. Furness, T.P. Robinson, T. Ehlers, R.B. Hubbard IV,
J.L. Arbiser, D.J. Goldsmith and J.P. Bowen
[Abstract] [Full
text article]
General Articles
The Design of Cationic Lipids for Gene Delivery Pp.375-394
B. Martin, M. Sainlos, A. Aissaoui, N. Oudrhiri, M. Hauchecorne,
J.-P. Vigneron, J.-M. Lehn and P. Lehn
[Abstract]
[Full text article]
Thalidomide as an Immunotherapeutic Agent: The
Effects on Neutrophil-Mediated Inflammation Pp.395-401
Kozo Yasui, Norimoto Kobayashi, Takashi Yamazaki, Kazunaga
Agematsu
[Abstract]
[Full text article]
Neurotransmitters and Chemokines Regulate Tumor
Cell Migration: Potential for a New Pharmacological Approach
to Inhibit Invasion and Metastasis Development Pp.403-411
Frank Entschladen, Theodore L. Drell IV, Kerstin Lang,
Jan Joseph, Kurt S. Zaenker
[Abstract]
[Full text article]
Abstracts
[Back to top]
Editorial
M. Rami Reddy
[Editorial
In PDF]
Advances in protein crystallography and molecular simulations
have greatly aided computer aided drug design paradigms and
the accuracy of binding affinity predictions. The methods
used in the discovery and/or optimization of a lead inhibitor
have ranged from graphical visualization of the ligand in
the binding site to calculation of relative binding affinities
using molecular dynamics simulations in conjunction with the
Free Energy Perturbation (FEP) approach. The aim of the Computer
Aided Drug Design (CADD) issue of Current Pharmaceutical Design
is to provide computational chemists and medicinal chemists
with a comprehensive review of the methods used for drug design.
While the FEP approach remains the method that consistently
generates the most accurate free energies, its high CPU requirements
and inability to evaluate compounds that differ significantly
in structure, clearly limit the impact and value of FEP calculations
on drug design. Accordingly, efforts are ongoing to develop
faster methods such as high-throughput docking, molecular
mechanics methods, etc. that have the potential to evaluate
a large number of compounds qualitatively.
The first article focuses on lead inhibitor optimization
strategies using the free energy perturbation approach and
molecular mechanics methods and evaluates the merits of each
method for predicting relative binding affinities of fructose
1,6-bisphosphatase inhibitors. The second article summarizes
all the published structural information for matrix metalloprotease
inhibitor complexes and the design of specific matrix metalloproteinase
inhibitors using structure-based drug design methods.The third
article focuses on various computational aspects of docking-based
virtual screening of small molecule databases. In addition
the article discusses the fundamental issues and challenges
associated with various docking methods. The fourth article
describes several computational techniques such as high-throughput
docking and similarity searching to identify potential lead
MurB inhibitors. The fifth article describes computer-based
strategies for modeling the interaction of agouti-related
protein (AGRP) and related peptide ligands with the AGRP-binding
site of murine melanocorin receptors. The final article describes
efforts to design and prepare fumagillin and curcumin analogs
and the antiangiogenic activities for a promising anti-cancer
treatment discovered using CADD methods.
Overall, this issue provides an extensive overview of the
scope and limitations of CADD methods. The authors contributing
to this issue are well-recognized leaders in this field of
research representing both academic institutions and pharmaceutical
industry. As an Executive Editor of Current Pharmaceutical
Design, I would like to thank the authors for their contributions.
I would also like to thank Dr. Mark Erion for his helpful
suggestions and his encouragement and support in editing this
CADD issue.
M. Rami Reddy, Ph. D.
Metabasis Therapeutics, Inc.
9390 Towne Centre Dr.
San Diego, CA 92121
USA
[Back to top]
Computer Aided Drug Design Strategies Used in the
Discovery of Fructose 1, 6-Bisphosphatase Inhibitors
M. Rami Reddy and Mark D. Erion
[Full text
article]
Computational assessment of the binding affinity of enzyme
inhibitors prior to synthesis is an important component of
computer-aided drug design (CADD) paradigms. The free energy
perturbation (FEP) methodology is the most accurate means
of estimating relative binding affinities between two inhibitors.
However, due to its complexity and computation-intensive nature,
practical applications are restricted to analysis of structurally-related
inhibitors. Accordingly, there is a need for methods that
enable rapid assessment of a large number of structurally-unrelated
molecules in a suitably accurate manner. In this review, the
FEP method is compared with molecular mechanics (MM) methods
to assess the advantages of each in the estimation of relative
binding affinities of inhibitors to an enzyme. Qualitative
predictions of relative binding free energies of fructose
1, 6-bisphosphatase inhibitors using MM methods are discussed
and compared with the corresponding FEP results. The results
indicate that the MM based methods and the FEP method are
useful in the qualitative and quantitative assessment of relative
binding affinities of enzyme inhibitors, respectively, prior
to synthesis.
[Back to top]
Recent Developments in the Design of Specific Matrix
Metalloproteinase Inhibitors aided by Structural and Computational
Studies
B. Govinda Rao
[Full text
article]
It has been 10 years since a 3-dimensional structure of the
catalytic domain of a Matrix Metalloprotease (MMP) was revealed
for the first time in 1994. More than 80 structures of different
MMPs in apo and inhibited forms, determined by X-ray crystallography
and NMR methods, have been published by the end of year 2003.
A large number of very potent inhibitors have been disclosed
in published and patent literature. Several MMP inhibitors
entered clinical trials for the treatment of cancer and arthritis.
Most of the first generation inhibitors have hydroxamic acid
as the Zinc-binding group and have limited specificity. With
the failure of these inhibitors in clinical trials, more efforts
have been directed to the design of specific inhibitors with
different Zn-binding groups in recent years. This review will
summarize all the published structural information and focus
on the inhibitors that were designed to take advantage of
the nonprime side of the MMP active site using structural
information and computational analysis. Representative structures
from all MMPs are aligned to a target structure to provide
a better understanding of the similarities and differences
of the active site pockets. This analysis supports the view
that the differences in the nonprime side pockets provide
better opportunities for designing inhibitors with higher
specificity. Published information on all the Zinc-binding
groups of MMP inhibitors is reviewed for the first time. Pros
and cons of inhibitors with non-hydroxamate Zinc-binding groups
in terms of specificity, toxicity and pharmacokinetic properties
are discussed.
[Back to top]
Docking: Successes and Challenges
Venkatraman Mohan, Alan C. Gibbs, Maxwell D.
Cummings, Edward P. Jaeger and Renee L. DesJarlais
[Full text
article]
The state of the art of various computational aspects of
docking-based virtual screening of database of small molecules
is presented. The review encompasses the different search
algorithms and the scoring functions used in docking methods
and their applications to protein and nucleic acid drug targets.
Recent progress made in the development and application of
methods to include target flexibility are summarized. The
fundamental issues and challenges involved in comparing various
docking methods are discussed. Limitations of current technologies
as well as future prospects are presented.
[Back to top]
Discovery Strategies in a BioPharmaceutical Startup: Maximising
your Chances of Success Using Computational Filters
A. Jennings and M. Tennant
[Full text
article]
Small research-based pharmaceutical start-ups often lack
the budget and do not have the infrastructure available to
apply all possible techniques for compound selection. This
review details our use of a range of techniques such as high-throughput
docking and similarity searching to maximize the success rate
when attempting to identify pharmaceutically relevant ligands
in a resource-constrained environment.
[Back to top]
Computer-Based Strategy for Modeling the Interaction
of AGRP and Related Peptide Ligands with the AGRP-Binding
Site of Murine Melanocortin Receptors
Xiang Wang and Nigel G.J. Richards
[Full text
article]
The hypothesis that the interaction of agouti-related protein
(AGRP) and the melanocortin-4 receptor (MC4R) modulates feeding
behavior in humans has stimulated the synthesis of conformationally
constrained peptides, peptoids and small molecules in efforts
to identify novel compounds that can potentially be used in
the clinical treatment of obesity and related eating disorders.
In addition, the availability of a high-resolution NMR structure
for the MC4R-binding domain of AGRP, and studies employing
site-specific murine MC4R mutants have identified key intermolecular
AGRP/MC4R interactions. It is therefore surprising that only
one, relatively unsophisticated, computer-based study has
been reported to obtain a model for the AGRP/mMC4R complex.
In this review we outline computer-based strategies for building
models of the AGRP/mMC4R and related peptide/mMC4R complexes,
and illustrate the strengths and limitations of sophisticated
molecular dynamics methods in obtaining information that might
form the basis of rational efforts to discover novel drugs
that selectively interact with melanocortin receptors.
[Back to top]
Antiangiogenic Agents: Studies on Fumagillin and Curcumin
Analogs
M.S. Furness, T.P. Robinson, T. Ehlers, R.B.
Hubbard IV, J.L. Arbiser, D.J. Goldsmith and J.P. Bowen
[Full text
article]
Cancer is a general term used to describe many disease states,
each of which are characterized by abnormal cell proliferation.
The causes which bring about this abnormal cellular behavior
are specific to each type of cancer. The success of tumor-targeted
therapy is limited by this diversity. One common denominator
for all types of cancer is the requirement of a suitable blood
supply. Therefore, tumor vasculature has emerged as a potential
target for therapeutic intervention. New blood vessel growth
from preexisting vasculature stimulated by biochemical signals
is termed angiogenesis. Tumor masses require a constant supply
of oxygen and nutrients, and a means of efficient waste removal
to ensure sustained development. Diffusion from nearby capillaries
can supply adequate nutrition for tumors less than 2 mm in
size, but for continued growth the tumors must develop their
own blood supply. Alteration of the delicate balance of angiogenic
stimulating factors and angiogenic inhibitors results in the
phenotypic change from quiescence to active endothelial proliferation.
To date, this angiogenic switch is not completely understood.
The goal of antiangiogenic therapy is to interfere with these
mechanisms and prevent tumor cells from developing a viable
blood supply. Fumagillin is a naturally occurring antifungal
agent. Curcumin is a natural product isolated from the spice
turmeric. Both compounds have been shown to have antiangiogenic
properties in vitro and in vivo. This paper
describes efforts to design and prepare fumagillin and curcumin
analogs and evaluate their corresponding antiangiogenic activities.
[Back to top]
The Design of Cationic Lipids for Gene Delivery
B. Martin, M. Sainlos, A. Aissaoui, N. Oudrhiri,
M. Hauchecorne, J.-P. Vigneron, J.-M. Lehn and P. Lehn
[Full text
article]
Synthetic gene delivery vectors are gaining increasing importance
in gene therapy as an alternative to recombinant viruses.
Among the various types of non-viral vectors, cationic lipids
are especially attractive as they can be prepared with relative
ease and extensively characterised. Further, each of their
constituent parts can be modified, thereby facilitating the
elucidation of structure-activity relationships. In this forward-looking
review, cationic lipid-mediated gene delivery will mainly
be discussed in terms of the structure of the three basic
constituent parts of any cationic lipid: the polar headgroup,
hydrophobic moiety and linker. Particular emphasis will be
placed on recent advances in the field as well as on our own
original contributions. In addition to reviewing critical
physicochemical features (such as headgroup hydration) of
monovalent lipids, the use of headgroups with known nucleic-acid
binding modes, such as linear and branched polyamines, aminoglycosides
and guanidinium functions, will be comprehensively assessed.
A particularly exciting innovation in linker design is the
incorporation of environment-sensitive groups, the intracellular
hydrolysis of which may lead to more controlled DNA delivery.
Examples of pH-, redox- and enzyme-sensitive functional groups
integrated into the linker are highlighted and the benefits
of such degradable vectors can be evaluated in terms of transfection
efficiency and cationic lipid-associated cytotoxicity. Finally,
possible correlations between the length and type of hydrophobic
moiety and transfection efficiency will be discussed. In conclusion
it may be foreseen that in order to be successful, the future
of cationic lipid-based gene delivery will probably require
the development of sophisticated virus-like systems, which
can be viewed as “programmed supramolecular systems”
incorporating the various functions required to perform in
a chronological order the different steps involved in gene
transfection.
[Back to top]
Thalidomide as an Immunotherapeutic Agent: The Effects
on Neutrophil-Mediated Inflammation
Kozo Yasui, Norimoto Kobayashi, Takashi Yamazaki,
Kazunaga Agematsu
[Full text
article]
Thalidomide was developed in the 1950s as a sedative drug
and withdrawn in 1961 because of its teratogenic effects,
but has been rediscovered as an immuno-modifying drug. It
has been administered successfully for the treatment of erythema
nodosum leprosum, aphthous ulceration in HIV disease, inflammatory
bowel diseases, and multiple myeloma. So far, investigations
into the mode of action of thalidomide have focused on lymphocytes
and vascular endothelial cells and have shown that this agent
inhibits the production of tumor necrosis factor (TNF)-α
and is an inhibitor of tumor angiogenesis.
Recently, other immunological effects of this drug have been
gaining attention, including attenuation of neutrophil activation
and inhibition of myelo-proliferative responses. In autoimmune
diseases, inflammation is characterized by an influx of granulocytes,
and the association of granulocytes with gastrointestinal
ulcer formation or rheumatic arthritis has been well documented.
The suppressive effect of thalidomide on the activation of
the nuclear transcription factor NF-κB
may explain these effects of thalidomide. NF-κB
is retained in the cytoplasm with IκBα,
and is activated by a wide variety of inflammatory stimuli
including TNF, IL-1 and endotoxin followed by its translocation
to the nucleus. Constitutive activation of NF-κB
has been detected in various inflammatory diseases, while
angiogenesis and organogenesis also require NF-κB
activation. Thalidomide, on the other hand, has been shown
to selectively suppress NF-κB
activation induced by inflammatory mediators. NF-κB
is known to be located downstream of proliferative and/or
survival signaling induced by growth factors, which regulate
anti-apoptotic genes. Myeloid cells in vitro, however,
have been found to proceed to apoptosis as the result of the
treatment with thalidomide and subsequent inactivation of
NF-κB.
These findings are consistent with clinical symptoms that
showed the recovery from leukocytosis and/or neutrophilia
after the administration of thalidomide. These findings shed
new light on the anti-inflammatory properties of thalidomide
and suggested that they may inhibit granulocyte-mediated tissue
injury.
[Back to top]
Neurotransmitters and Chemokines Regulate Tumor Cell Migration:
Potential for a New Pharmacological Approach to Inhibit Invasion
and Metastasis Development
Frank Entschladen, Theodore L. Drell IV, Kerstin
Lang, Jan Joseph, Kurt S. Zaenker
[Full text
article]
The migration of tumor cells is a prerequisite for tumor
cell invasion and metastasis development, which accounts for
over 90% of cancer mortality. Therefore a major focus of current
tumor biological research is the study of those actors that
regulate tumor cell migration. Those chemokines and neurotransmitters
that bind to G-protein coupled receptors (also known as serpentine
receptors) are the most prominent of these factors. Neurotransmitters
have been identified that have not only a stimulatory (e.g.
norepinephrine) effect, but an inhibitory effect (e.g. GABA)
as well. This is an especially fortuitous development, because
many known agonists and antagonists of neurotransmitter receptors
are currently being successfully used in the treatment of
other pathological conditions (e.g. β-blockers in the treatment
of cardiovascular diseases). Likewise, chemokine receptor
antagonists, which are under development for the treatment
of HIV or rheumatoid arthritis, may be effective tools for
the inhibition of chemokine-driven tumor cell migration as
well. A further approach to inhibit tumor cell migration arises
from the investigation of the relevant signal transduction
pathways. The PKC alpha, for example, is a key enzyme in the
regulation of tumor cell migration, but not of leukocyte migration.
It thus offers a selective target opportunity for specific
pharmacological agents to interfere with tumor cell migration.
In this review we therefore summarize the current findings
on those serpentine receptors involved in the neurotransmitter-
and chemokine-regulated tumor cell migration, on the underlying
signal transduction pathways, and on the opportunities to
inhibit tumor cell migration and ultimately metastasis development
with pharmaceutical agents.
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