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Frontiers in Medicinal
Chemistry
ISBN: 90-77527-07-9
Frontiers in Medicinal Chemistry
Volume 3, 2006
Contents
Editorial
Infectious Diseases
Structure and Function of HIV-1 Integrase: An
Update Pp. 3-22
Thang K. Chiu and David R. Davies
[Abstract]
Anti-HIV Drugs and Resistance: Inhibitors of HIV-1
Reverse
Transcriptase and Protease Pp. 23-44
Tomozumi Imamichi
[Abstract]
Cardiovascular Diseases
Drug Development and the Importance of Ethnicity:
Lessons from Heart Failure Management and Implications for
Hypertension Pp. 45-58
Michael D. Sosin, Gurbir S. Bhatia, Gregory Y.H. Lip and Russell
C. Davis
[Abstract]
Gene Therapy for Cardiovascular Diseases Pp.
59-85
Marcin Gruchala, Himadri Roy, Shalini Bhardwaj and Seppo Ylä-Herttuala
[Abstract]
Design and Discovery of Novel Antihypertensive Drugs
Through Conformation and Bioactivity Studies Pp.
87-111
Thomas M. Mavromoustakos, Maria V. Zervou and Panagiotis G.
Zoumpoulakis
[Abstract]
Novel Antiarrhythmic Compounds with Combined Class
IB and Class III Mode of Action Pp. 113-124
Péter Mátyus, Ildikó Varga, Tivadar Rettegi,
Antal Simay, Péter Kovács, László
Károlyházy, Ákos Kocsis, Szilvia Vajda,
András Varró, István Pénzes and
Julius Gy. Papp
[Abstract]
A1 Adenosine Receptor Agonists: Medicinal
Chemistry and
Therapeutic Potential Pp. 125-151
Sally A. Hutchinson and Peter J. Scammells
[Abstract]
Central Nervous System Disorders
Are the Extracellular Pathways a Conduit for the
Delivery of Therapeutics to the Brain? Pp.153-161
William A. Banks
[Abstract]
A Review of Neuroprotective Agents Pp. 163-194
Margaret A. Brimble and Mark S. Levi
[Abstract]
Design of Ligands for the Nicotinic Acetylcholine
Receptors: The Quest for Selectivity Pp.195-247
William H. Bunnelle, Michael J. Dart and Michael R. Schrimpf
[Abstract]
New Trends in the Design of Drugs Against Alzheimer’s
Disease Pp. 249-284
Pierre Francotte, Pascal de Tullio, Pierre Fraikin and Bernard
Pirotte
[Abstract]
Endocrine and Metabolic Disorders
Development of Melanocortin Receptor Selective Ligands
Pp. 285-334
Boman G. Irani, Jerry R. Holder, Aleksandar Todorovic, Andrzej
M. Wilczynski, Christine G. Joseph, Krista R. Wilson and Carrie
Haskell-Luevano
[Abstract]
Inhibition of Protein Tyrosine Phosphatase 1B
for the Treatment of Diabetes and Obesity Pp.
335-368
Zhonghua Pei, Gang Liu, Thomas H. Lubben andBruce G. Szczepankiewicz
[Abstract]
Immunology
The Impact of Infection on the Incidence of Autoimmune
Disease Pp. 369-382
Thomas D.C. Thomas, Paola Zaccone, David W. Dunne and Anne
Cooke
[Abstract]
Transcription Factors in Autoimmune Diseases
Pp. 383-397
Martin Eggert, Andreas Klüter, Uwe K. Zettl and Gunther
Neeck
[Abstract]
Oncology
Small Molecule FLT3 Tyrosine Kinase Inhibitors
Pp. 399-416
Mark Levis and Donald Small
[Abstract]
Potentiality and Limitations of a Strategy for the
Control of Cell Proliferation: The Block of Ca2+
Entry Pp.417-433
Luca Munaron, Susanna Antoniotti, Alessandra Fiorio Pla and
Davide Lovisolo
[Abstract]
An Expanding Appreciation of the Role Chemokine
Receptors Play in Cancer Progression Pp. 435-454
O.M. Zack Howard and Carole L. Galligan
[Abstract]
Enabling Technologies
Structural Bioinformatics and its Impact to Biomedical Science
and Drug Discovery Pp. 455-502
Kuo-Chen Chou
[Abstract]
Recent Advances in Chemical Genomics Pp.
503-550
György Dormán, Péter Krajcsi, László
G. Puskás, Zoltán Kovári,
Zsolt Lo"rincz, László Ürge and Ferenc
Darvas
[Abstract]
Predicting Molecular Interactions In Silico:
I. An Updated Guide to Pharmacophore Identification and its
Applications to Drug Design Pp. 551-584
Oranit Dror, Alexandra Shulman-Peleg, Ruth Nussinov and Haim
J. Wolfson
[Abstract]
Predicting Molecular Interactions In Silico:
II. Protein-Protein and Protein-Drug Docking Pp.
585-613
Dina Schneidman-Duhovny, Ruth Nussinov and Haim J. Wolfson
[Abstract]
In Silico Methods for Predicting
Ligand Binding Determinants of Cytochromes P450
Pp. 615-652
Marcel J. de Groot, Stewart B. Kirton and Michael J. Sutcliffe
[Abstract]
Trends in Hit-to-Lead: An Update Pp.
653-673
Benoit Deprez and Rebecca Deprez-Poulain
[Abstract]
Recent Development and Application of Virtual Screening
in Drug Discovery: An Overview Pp. 675-703
Tingjun Hou and Xiaojie Xu
[Abstract]
Others
Biology of Heme in Health and Disease
Pp. 705-714
Nastiti Wijayanti and Stephan Immenschuh
[Abstract]
Abstracts
[Back to top]
Editorial
Frontiers in Medicinal Chemistry, Vol.
3 continues the tradition of the two previous volumes
in providing a comprehensive selection of manuscripts involving
diverse therapeutic areas as well as a section on important
enabling technologies. Although the topics covered were selected
from the Bentham journals “Current Medicinal Chemistry”,“Current
Topics in Medicinal Chemistry” and “Current
Pharmaceutical Design”, each of the authors has
had the opportunity to update their original contributions
with additional information or commentary, and many have chosen
to do so. Therefore, there is a substantial amount of new
material in these reviews that has not been published previously.
This volume contains 26 chapters arranged in eight sections.
The first section covers the area of Infectious Diseases with
manuscripts on HIV-1 integrase and drug resistance mediated
by HIV-1 reverse transcriptase and HIV protease inhibitors.
The next section is on Cardiovascular Diseases which addresses
ethnicity in heart failure management and hypertension, gene
therapy, novel antihypertensive agents, combined Class IB
and Class III antiarrhythmics, and the adenosine A1 receptor.
The section on Central Nervous System Disorders then starts
with a review on extracellular transport into the CNS which
is a nontraditional approach to the delivery of useful therapeutics
across the blood brain barrier. This is followed by articles
that review neuroprotective agents, the nicotinic acetylcholine
receptor and Alzheimer’s disease. The Endocrine and
Metabolic Disorders section highlights melanocortin receptors
and protein tyrosine phosphatase 1B inhibitors for diabetes
and obesity. The Immunology section addresses autoimmune disease
and transcription regulators. In the Oncology section are
found manuscripts on FLT3 tyrosine kinase inhibitors, Ca2+
channel blockade, and chemokine receptors. The Enabling Technologies
section is the longest one with seven manuscripts, reflecting
the importance of new approaches to conduct modern drug discovery
and medicinal chemistry research. The topics covered include
bioinformatics, chemical genomics, trends in hit-to-lead work,
virtual screening, and computational approaches to pharmacophore
identification, protein-protein and protein-drug interactions,
and cytochrome P450s. Finally, the biology of the heme protein
in health and disease is reviewed as well.
We thank the authors, who contributed to this volume, and
congratulate them for the high quality of their work. We also
thank Bentham for sponsoring this book series. We expect that
Frontiers in Medicinal Chemistry
will continue to be published on an annual basis with timely
and helpful reviews in areas of keen interest to practicing
medicinal chemists
throughout the world.
ATTA-UR-RAHMAN
Advisor to the Prime Minister on Science &
Technology
Higher Education Commission
International Center for Chemical Sciences
Pakistan
ALLEN B. REITZ
Johnson & Johnson
USA
M. IQBAL CHOUDHARY
International Center for Chemical Sciences
Pakistan
CHERYL P. KORDIK
Johnson & Johnson
USA
[Back to top]
Structure and Function of HIV-1 Integrase: An Update
Thang K. Chiu and David R. Davies
HIV-1 integrase is a multidomain enzyme which is required
for the integration of viral DNA into the host genome. It
is one of three enzymes of HIV, the others being Reverse Transcriptase
and Protease. It is an attractive target for therapeutic drug
design. The enzyme consists of three domains. The N-terminal
domain has a His2Cys2 motif which chelates
zinc, the core domain has the catalytic DDE motif which is
required for its enzymatic activity, and the C-terminal domain
has an SH3-like fold which binds DNA nonspecifically. We review
the structures of various integrase fragments, the core domain
with inhibitors bound, and propose a model for DNA binding.
[Back to top]
Anti-HIV Drugs and Resistance: Inhibitors of HIV-1
Reverse
Transcriptase and Protease
Tomozumi Imamichi
Currently, 20 drugs have been approved for Human Immunodeficiency
Virus type-1 (HIV-1) clinical therapy. These drugs inhibit
HIV-1 reverse transcriptase, protease, or virus entry. Introduction
of a combination therapy with reverse transcriptase inhibitors
and protease inhibitors has resulted in a drastic decrease
in HIV-1 related mortality. Although the combination therapy
can suppress viral replication below detection levels in current
available assays, low levels of on-going viral replication
still persist in some patients. Long-term administration of
the combination therapy may increase selective pressure against
viruses, and subsequently induce emergence of multiple drug-resistant
HIV-1 variants. Attempts have been made to design novel antiretroviral
drugs that would be able to suppress replication of the resistant
variants. At present, several investigational drugs are being
tested in clinical trials. These drugs target not only the
resistant variants, but also improvement in oral bioavilability
or other viral proteins such as HIV-1 integrase, ribonuclease
H, and HIV-1 entry (CD4 attachment inhibitors, chemokine receptors
antagonists, and fusion inhibitors). Understanding mechanism(s)
of action of the drugs and mechanisms of drug resistance is
necessary for successful designs in the next generation of
anti-HIV-1 drugs. In this review, the mechanisms of action
of reverse transcriptase- and protease-inhibitors, and the
mechanism of resistance to these inhibitors, are described.
[Back to top]
Drug Development and the Importance of Ethnicity:
Lessons from Heart Failure Management and Implications for
Hypertension
Michael D. Sosin, Gurbir S. Bhatia, Gregory Y.H. Lip and Russell
C. Davis
Heart failure is a common condition, associated with both
poor prognosis and poor quality of life. In contrast to all
other cardiovascular diseases, the prevalence of heart failure
is increasing in the western world, and is likely to continue
to do so as the population ages. In the UK, a significant
proportion of patients with heart failure come from South
Asian and African Caribbean ethnic groups. A large body of
evidence exists that there may be epidemiological and pathophysiological
differences between patients with heart failure from different
ethnic groups. Treatments such as ACE inhibitors, which are
now part of standard heart failure therapy, have an evidence
base consisting of trials in patients of almost exclusively
white ethnicity. Such treatments may not be equally effective
in patients from other ethnic groups. This review will discuss
the current evidence for heart failure management with respect
to ethnicity, and consider the implications for future drug
development and implications for antihypertensive therapy.
[Back to top]
Gene Therapy for Cardiovascular Diseases
Marcin Gruchala, Himadri Roy, Shalini Bhardwaj and Seppo Ylä-Herttuala
Gene therapy is a rapidly evolving field of medicine, which
potentially offers new treatments for cardiovascular diseases.
With the use of gene transfer methods it is possible to modify
somatic cells in blood vessels and myocardium to overexpress
or inhibit pathologically important proteins and achieve therapeutic
effects. Prevention of restenosis after vascular interventions
such as percutanous coronary angioplasty (PTCA), percutanous
peripheral angioplasty (PTA) or stent implantation, prevention
of venous grafts failure and therapeutic angiogenesis are
the major aims of experimental studies and clinical gene therapy.
The promise of gene therapy in the treatment of cardiovascular
diseases remains high. Experimental studies have established
the proof of principle that gene transfer to cardiovascular
system can achieve therapeutic effects. First human clinical
trials provided the initial evidence of the feasibility and
safety of the novel therapy. There are also first successful
reports on the prevention of neointimal hyperplasia and promotion
of therapeutic angiogenesis in clinical trials. However, there
are still important questions regarding utility, efficiency
and safety of gene therapy in the treatment of cardiovascular
diseases. In this review we discuss the rapid progress in
cardiovascular gene therapy, the development of delivery systems
and vectors, most promising therapeutic genes and results
of the recent human clinical trials.
[Back to top]
Design and Discovery of Novel Antihypertensive Drugs
Through Conformation and Bioactivity Studies
Thomas M. Mavromoustakos, Maria V. Zervou and Panagiotis G.
Zoumpoulakis
Peptidomimitism is applied to the medicinal chemistry in
order to synthesize drugs that devoid of the disadvantages
of peptides. AT1 antagonists constitute a new generation
of drugs for the treatment of hypertension designed and synthesized
to mimic the C-terminal segment of Angiotensin II and to block
its binding action on AT1 receptor. An effort was
made to understand the molecular basis of hypertension by
studying the conformational analysis of Ang II and its derivatives
as well as the AT1 antagonists belonging to SARTANs
class of molecules. Such studies offer the possibility to
reveal the stereoelectronic factors responsible for bioactivity
of AT1 antagonists and to design and synthesize
new analogs. An example will be given which proves that drugs
with better pharmacological and financial profiles may arise
based on this rational design.
[Back to top]
Novel Antiarrhythmic Compounds with Combined Class
IB and Class III Mode of Action
Péter Mátyus, Ildikó Varga, Tivadar Rettegi,
Antal Simay, Péter Kovács, László
Károlyházy, Ákos Kocsis, Szilvia Vajda,
András Varró, István Pénzes and
Julius Gy. Papp
Cardiac arrhythmias represent a major area of cardiovascular
research, and for drug therapy, a large choice of antiarrhythmic
agents have been available. However, clinical trials with
antiarrhythmic drugs have recently indicated that serious
side effects may considerably limit the use of various antiarrhythmic
agents, in particular, for preventing arrhythmia-related mortality.
Amiodarone with its complex mode of action, while exerting
a strong and favorable antiarrhythmic action, posseses extracardiac
untoward side effects originating from its chemical structure.
In this paper, we report on our attempt to develop conceptually
new, therapeutically valuable antiarrhythmic compounds, in
which Class I/B and Class III features were combined into
single molecules bearing no structural resemblance to amiodarone.
Synthesis and pharmacological screening of series of N-(phenylalkyl)-N-(phenoxyalkyl)amines
led us to discover some new promising compounds with the required
dual mode of action. GYKI-16638, selected for further investigation,
was also found to possess a remarkable in vivo antiarrhythmic
effect, and it is now considered as a safe new antiarrhythmic
drug candidate.
[Back to top]
A1 Adenosine Receptor Agonists: Medicinal
Chemistry and
Therapeutic Potential
Sally A. Hutchinson and Peter J. Scammells
Adenosine receptors are widely distributed in the body and
modulate numerous physiological processes. Four receptor subtypes
(termed A1, A2A, A2B and
A3) have been identified based on their pharmacological
profile and cloning. Activation of the A1 adenosine
receptors produces a number of effects including a reduction
in heart rate and atrial contractility, the attenuation of
the stimulatory actions of catecholamines on the heart as
well as a reduction of lipolysis in adipose tissue. As a result,
A1AR agonists have been targeted as anti-arrhythmic
and cardioprotective agents. This review discusses the synthesis,
structure-activity relationships and therapeutic potential
of A1AR agonists.
[Back to top]
Are the Extracellular Pathways a Conduit for the Delivery
of Therapeutics to the Brain?
William A. Banks
Most drugs with central nervous system (CNS) activity enter
the brain either by diffusing across the membranes which comprise
the blood-brain barrier (BBB) or by being transported by carrier
systems across those membranes. Substances which cannot cross
the BBB by one of these mechanisms, like serum albumin, are
virtually excluded from the CNS. However, this exclusion is
not absolute. Cerebrospinal fluid (CSF) levels of albumin,
for example, are about 0.5% those of serum levels. Albumin
enters the CNS through a variety of pathways collectively
termed the extracellular pathways. Any circulating substance
can, in theory, use these pathways to enter the CNS. But,
traditional drug development has ignored this pathway. To
approach even the CSF/serum ratio of 0.5%, a candidate therapeutic
would need to meet several criterion: long half-life in blood,
small volume of distribution, high potency in the CNS, and
absence of brain-to-blood efflux. Two emerging therapeutics
which are likely exerting their CNS effects by way of the
extracellular pathways are antibodies directed against amyloid
beta protein (ABP) and erythropoietin (Epo) used in the treatment
of stroke. These examples suggest that the extracellular pathways
are an option for the delivery of certain therapeutics to
the brain.
[Back to top]
A Review of Neuroprotective Agents
Margaret A. Brimble and Mark S. Levi
The brain remains an area where little corrective surgery
can be performed and the reversal of damage is almost impossible.
Recently, reports of agents offering neuroprotection have
begun to appear in the literature. The concept of neuroprotection
is the administration of some agent, which should reverse
some of the damage or prevent further damage. Some agents
offer protection against cell degeneration to the neuronal
cells. Still other agents specifically protect the dopamine
neurons and the retina. The majority of neuroprotective agents
are antioxidants. An immunosuppressive immunophilin ligand,
NOS inhibitor, σ-1
modulator, AMPA antagonist and Ca2+ channel blocker
have all shown neuroprotective activity. An oestrogen agonist
and two glycoprotein IIb/IIIa antagonists also exhibit neuroprotective
activity. Most of the synthetic compounds presented were not
originally designed as neuroprotective agents but were found
to possess neuroprotective activity in later studies. Many
of these compounds are biologically active natural products,
either plant extracts or endogenous peptides/proteins. This
chapter will present the most recent reports on these agents.
[Back to top]
Design of Ligands for the Nicotinic Acetylcholine
Receptors: The Quest for Selectivity
William H. Bunnelle, Michael J. Dart and Michael R. Schrimpf
In the last decade, nicotinic acetylcholine receptors (nAChRs)
have emerged as important targets for drug discovery. The
therapeutic potential of nicotinic agonists depends substantially
on the ability to selectively activate certain receptor subtypes
that mediate beneficial effects. The design of such compounds
has proceeded in spite of a general shortage of data pertaining
to subtype selectivity. Medicinal chemistry efforts have been
guided principally by binding affinities to the α4β2
and/or α7
subtypes, even though these are not predictive of agonist
activity at either subtype. Nevertheless, a diverse family
of nAChR ligands has been developed, and several analogs with
promising therapeutic potential have now advanced to human
clinical trials. This paper provides an overview of the structure-affinity
relationships that continue to drive development of new nAChR
ligands.
[Back to top]
New Trends in the Design of Drugs Against Alzheimer’s
Disease
Pierre Francotte, Pascal de Tullio, Pierre Fraikin and Bernard
Pirotte
First described by Alois Alzheimer in 1907, Alzheimer’s
disease (AD) is the most common dementia type, affecting approximately
20 million people worldwide. As the population is getting
older, AD is a growing health problem.
AD is currently treated by symptomatic drugs, the acetylcholinesterase
inhibitors, based on the cholinergic hypothesis (1976).
During the past decade, advances in neurobiology have conducted
to the identification of new targets. Although some of these
innovative approaches tend to delay onset of AD, others are
still symptomatic.
In this review, we present an overview of the several strategies
and new classes of compounds against AD.
[Back to top]
Development of Melanocortin Receptor Selective Ligands
Boman G. Irani, Jerry R. Holder, Aleksandar Todorovic, Andrzej
M. Wilczynski, Christine G. Joseph, Krista R. Wilson and Carrie
Haskell-Luevano
The melanocortin pathway consists of endogenous agonists,
antagonists, G-protein coupled receptors (GPCRs), and auxiliary
proteins. This pathway has been identified to participate
physiologically in numerous biological pathways including
energy homeostasis, pigmentation, sexual function, inflammation,
cardiovascular function, adrenal function, sebaceous gland
lipid production, just to list a few. During this past decade,
a clear link between the melanocortin-4 receptor (MC4R) and
obesity, in both mice and humans via the regulation of food
intake and energy homeostasis, has made this pathway the target
of many academic and industrial research endeavors in attempts
to develop potent and selective MC4R small molecules as anti-obesity
therapeutic agents. Herein, we attempt to summarize the known
proteins that constitute the melanocortin system and discuss
advances in peptide and non-peptide drug discovery.
[Back to top]
Inhibition of Protein Tyrosine Phosphatase 1B for
the Treatment of Diabetes and Obesity
Zhonghua Pei, Gang Liu, Thomas H. Lubben andBruce G. Szczepankiewicz
Type 2 diabetes is a prevalent disease which afflicts over
150 million people worldwide and there is a great medical
need for new therapeutic agents to treat it. Inhibition of
protein tyrosine phosphatase 1B (PTP1B) has emerged as a highly
validated, attractive approach for the treatment of not only
type 2 diabetes but also obesity. Discovery of small-molecule
inhibitors has been pursued extensively in both academia and
industry and a number of very potent and selective inhibitors
have been identified. With X-ray crystallography, the binding
modes of several classes of inhibitors have been elucidated.
This has resulted in significant progress in understanding
important interactions between inhibitors and specific residues
of PTP1B, which could help the design of future inhibitors.
However, since the active site of PTP1B that most of these
inhibitors bind to is highly hydrophilic, it remains a challenge
to identify inhibitors with both excellent in
vitro potency and drug-like physiochemical properties,
which would lead to significant in vivo activities.
[Back to top]
The Impact of Infection on the Incidence of Autoimmune
Disease
Thomas D.C. Thomas, Paola Zaccone, David W. Dunne and Anne
Cooke
Falling infection rates in the developed world are being
matched by a rapidly rising incidence of allergic and autoimmune
diseases. This review explores the hypothesis that there is
a causal link between these phenomena and that infections
can prevent the onset of autoimmune disease. The hypothesis
is discussed with particular reference to Type I diabetes
in the NOD mouse and the ability of the helminth infection
Schistosoma mansoni to prevent its onset. The article
addresses the possible mechanisms that underly this protection.
The effects of protective pathogen-derived agents on key cells
of the innate immune system such as dendritic cells are distinct
and include the production of anti-inflammatory cytokines
such as IL-10. The most likely mechanisms by which these innate
changes prevent the subsequent adaptive autoimmune destruction
are: (1) the production of systemically high levels of cytokines
that oppose the production of cytokines that drive the autoimmune
process – possibly via the action of natural
killer T (NKT) cells (2) the induction of regulatory T cells
that inhibit the action of autoreactive cells and (3) the
production of pathogen-specific T cells that are not autoreactive
and compete with autoreactive cells for survival signals such
as cytokines and T cell receptor ligation.
[Back to top]
Transcription Factors in Autoimmune Diseases
Martin Eggert, Andreas Klüter, Uwe K. Zettl and Gunther
Neeck
The analysis of the molecular basis of autoimmune diseases
is currently under intense investigation. The identification
of novel mechanisms underlying the pathogenesis of these diseases
generates the possibility for the development of new therapeutic
agents. In this review we summarize the results leading to
novel insights concerning the molecular processes involved
in the pathogenesis of rheumatoid arthritis, systemic lupus
erythematodes, multiple sclerosis and diabetes type 1. We
focus on the role of transcription factors such as nuclear
factor kappa B, activator protein 1, peroxisome proliferator-activated
receptor, vitamin D receptor and the glucocorticoid receptor
that mediate pro- and anti-inflammatory effects and therefore
represent direct or indirect targets for therapeutic intervention.
[Back to top]
Small Molecule FLT3 Tyrosine Kinase Inhibitors
Mark Levis and Donald Small
Activating mutations of FLT3 (FMS-Like
Tyrosine kinase-3) are the most common molecular
abnormality in acute myeloid leukemia (AML). Their presence
is associated with a worse prognosis, and the recognition
of this has led to the development of several new small molecule
FLT3 tyrosine kinase inhibitors. In this review, we summarize
these developments and compare and contrast these novel agents
both with regards to the assays used to characterize them
as well as to their clinical potential.
[Back to top]
Potentiality and Limitations of a Strategy for the
Control of Cell Proliferation: The Block of Ca2+
Entry
Luca Munaron, Susanna Antoniotti, Alessandra Fiorio Pla and
Davide Lovisolo
Ca2+ signalling is involved in virtually all cellular
processes: among the others, it controls cell survival, proliferation
and death regulating a plethora of intracellular enzymes located
in the cytoplasm, nucleus and organelles.
Changes in the cytosolic free Ca2+ concentration
may be due either to release from the intracellular Ca2+
stores or to influx from the extracellular medium, through
the opening of plasmamembrane calcium-permeable channels.
In particular, Ca2+ entry from the extracellular
space is a mechanism able to sustain long lasting intracellular
Ca2+ elevations: this signal, activated by many
growth factors and mitogens in normal and tumoral tissues,
is linked to DNA transcription and duplication, finally leading
to cell proliferation.
In the last years many informations have been provided about
the transduction mechanisms related to Ca2+ entry
induced by mitogenic factors, mostly binding to tyrosine kinase
receptors, but also to G-protein coupled ones. Nevertheless,
some key points remain to be fully clarified: among them,
the molecular structure of the Ca2+ channels involved,
their regulation by intracellular messengers, and the modes
through which specificity is achieved.
The increasing knowledge on Ca2+ entry-dependent
control of proliferation may provide a more satisfactory understanding
of pathological alterations, including cancer progression
and angiogenesis. A detailed description of the mechanisms
that trigger Ca2+ entry, and in particular the
definition of calcium-permeable channels and their modulators
at the molecular levels, will greatly improve our possibility
to take advantage of Ca2+ entry regulation as a
therapeutic approach for the control of cell proliferation,
designing antibodies or molecules with low side effects and
specific channel blocker functions. The review will focuse
on this topic.
[Back to top]
An Expanding Appreciation of the Role Chemokine Receptors
Play in Cancer Progression
O.M. Zack Howard and Carole L. Galligan
The contribution of small molecular weight chemoattractant
cytokines (chemokines) and their receptors in the trafficking
of tumor, immune and vascular cells pertaining to the development
and progression of cancer has begun to be investigated. The
current literature indicates that interactions between the
immune network, angiogenic and cell survival cascades are
important for the trafficking and progression of human cancer
and that chemokines and chemokine receptors play a central
role in these complex inter-related pathways. Several therapeutic
approaches have been reviewed and suggest that the most promising
arise from the development of combinations of chemokine receptor
antagonists.
[Back to top]
Structural Bioinformatics and its Impact to Biomedical
Science and Drug Discovery
Kuo-Chen Chou
During the last two decades, the number of sequence-known
proteins has increased rapidly. In contrast, the corresponding
increment for structure-known proteins is much slower. The
unbalanced situation has critically limited our ability to
understand the molecular mechanism of proteins and conduct
structure-based drug design by timely using the updated information
of newly-found sequences. Therefore, it is highly desired
to develop an automated method for fast deriving the 3D (dimensional)
structure of a protein from its sequence. Under such a circumstance,
the structural bioinformatics was emerging naturally as the
times required. In this review, three main strategies developed
in structural bioinformatics, i.e., pure energetic approach,
heuristic approach, and homology modeling approach, as well
as their underlying principles, are briefly introduced. Meanwhile,
a series of demonstrations are presented to show how the structural
bioinformatics has been applied to timely derive the 3D structures
of some functionally important proteins, helping to understand
their action mechanisms and stimulating the course of drug
discovery. Also, the limitation of these approaches and the
future challenges of structural bioinformatics are briefly
addressed.
[Back to top]
Recent Advances in Chemical Genomics
György Dormán, Péter Krajcsi, László
G. Puskás, Zoltán Kovári,
Zsolt Lo"rincz, László Ürge and Ferenc
Darvas
Chemical genomics, which utilizes specially designed small
chemical compounds early in the discovery phase of new drugs
to explore the life science at various levels, can address
biological questions that are not amenable to genetic manipulation
or functional genomics/proteomics approaches. Following the
development of HT phenotypic assays and DNA expression analysis,
the integration of cell-based assays with activity / affinity-based
approaches allows us to interrogate the cells by analyzing
phenotypic alterations, changes of transcript signature or
detecting the differences in protein expression levels. Furthermore,
activity / affinity-based techniques directly provide a druggable
subset of gene products which interact with small molecules,
greatly reducing the complexity of analyzing the proteome.
In this paper, we give an account of the recent advances (approaches
and strategies) in the field of chemical genomics, and discuss
how these approaches enable the investigator to obtain a novel
therapeutically relevant target as well as drug candidates
acting on them in a target-specific manner. This novel post-genomic
discovery strategy, where target identification/ validation
is carried out by interactions with small molecules, could
significantly reduce the time-scale for early drug discovery,
and increase the success rate of finding novel, druggable
targets, as well as more specific drug candidates.
[Back to top]
Predicting Molecular Interactions In Silico:
I. An Updated Guide to Pharmacophore Identification and its
Applications to Drug Design
Oranit Dror, Alexandra Shulman-Peleg, Ruth Nussinov and Haim
J. Wolfson
A major goal in contemporary drug design is to develop new
ligands with high affinity of binding toward a given protein
receptor. Pharmacophore, which is the three-dimensional arrangement
of essential features that enable a molecule to exert a particular
biological effect, is a very useful model for achieving this
goal. If the three-dimensional structure of the receptor is
known, pharmacophore is a complementary tool to standard techniques,
such as docking. However, frequently the structure of the
receptor protein is unknown and only a set of ligands together
with their measured binding affinities towards the receptor
is available. In such a case, a pharmacophore-based strategy
is one of the few applicable tools.
Here, we present a broad, yet concise, guide to pharmacophore
identification and review a sample of applications for drug
design. In particular, we present the framework of the algorithms,
classify their modules and point out their advantages and
challenges.
[Back to top]
Predicting Molecular Interactions In Silico:
II. Protein-Protein and Protein-Drug Docking
Dina Schneidman-Duhovny, Ruth Nussinov and Haim J. Wolfson
This article reviews the docking field starting from basic
docking algorithms and describing the latest advances. We
present the algorithmic framework and classify the state of-the-art
methods. We point out the bottlenecks of the methods, like
flexibility, absence of absolute scoring functions and explain
what types of information can potentially be added to improve
the results.
[Back to top]
In Silico Methods for Predicting
Ligand Binding Determinants of Cytochromes P450
Marcel J. de Groot, Stewart B. Kirton and Michael J. Sutcliffe
A large number of computational methodologies have been used
to predict, and thus help explain, the metabolism catalysed
by the enzymes of the cytochrome P450 superfamily (P450s).
The methodologies and resulting models are summarized. This
illustrates that investigations so far have focused on a small
number of the many P450s; specifically those that are involved
in drug metabolism. The models have evolved from simple comparisons
of known substrates to more elaborate experiments that require
considerable computer power. These models help to explain
and, more importantly, predict the involvement of P450s in
the metabolism of specific compounds.
[Back to top]
Trends in Hit-to-Lead: An Update
Benoit Deprez and Rebecca Deprez-Poulain
The goal of this paper is to review the variety of approaches
used to improve lead generation, in terms of cost, time and
risk management. Our analysis shows that successful lead generation
requires not only an accurate definition of the needs (to
define the most relevant assay protocols and readouts), but
most of all a good hit as a starting point. It also appears
that teams where techniques and knowledge are combined, are
more successful in that difficult game.
[Back to top]
Recent Development and Application of Virtual Screening
in Drug Discovery: An Overview
Tingjun Hou and Xiaojie Xu
Virtual screening, especially the structure-based virtual
screening, has emerged as a reliable, cost-effective and time-saving
technique for the discovery of lead compounds. Here, the basic
ideas and computational tools for virtual screening have been
briefly introduced, and emphasis is placed on aspects of recent
development of docking-based virtual screening, scoring functions
in molecular docking and ADME/Tox-based virtual screening
in the past three years (2000 to 2003). Moreover, successful
examples are provided to further demonstrate the effectiveness
of virtual screening in drug discovery.
[Back to top]
Biology of Heme in Health and Disease
Nastiti Wijayanti and Stephan Immenschuh
Heme is an essential molecule with contradictory biological
functions. In hemoproteins such as hemglobin and cytochromes
protein-bound heme is a prosthetic group serving physiological
functions as a transporter for oxygen and electrons. On the
other hand free heme can have deleterious effects by generating
reactive oxygen species that cause oxidative stress. Consequently,
heme homeostasis of the cell must be tightly controlled via
regulation of its enzymatic biosynthesis and degradation that
are differentially regulated in liver and erythroid cells.
Accumulating evidence indicates that heme has potent proinflammatory
effects and is involved in the pathogenesis of diseases such
as rhabdomyolysis, sickle cell disease and atherosclerosis.
The regulation of gene expression by heme in yeast and mammals
and the underlying molecular mechanisms are presented. Finally,
we discuss the functional significance of the heme-degrading
enzyme heme oxygenase-1 and that of heme-binding proteins
for the regulation of heme homeostasis.
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