Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 35, 2006
Contents
SARS-CoV: A Scenario of Modern Drug Design
Executive Editor: X. Huang
Editorial Pp. 4537-4538
An Overall Picture of SARS Coronavirus (SARS-CoV)
Genome-Encoded Major Proteins: Structures, Functions and Drug
Development Pp. 4539-4553
S. Chen, H. Luo, L. Chen, J. Chen, J. Shen, W. Zhu, K.
Chen, X. Shen and H. Jiang
[Abstract]
Quaternary Structure, Substrate Selectivity and Inhibitor
Design for SARS 3C-Like Proteinase Pp. 4555-4564
L. Lai, H. Chen, P. Wei, C. Huang, S. Liu, K. Fan, L.
Zhou, X. Han, Z.Liu, J. Pei and Y. Liu
[Abstract]
Bioinformatics Research on the SARS Coronavirus (SARS_CoV)
in China Pp. 4565-4572
P. Hao, M. Chen, G. Zhang, W. He and Y. Li
[Abstract]
Drug Design Targeting the Main Protease, the Achilles'
Heel of Coronaviruses Pp. 4573-4590
H. Yang, M. Bartlam and Z. Rao
[Abstract]
The Heterodimeric Sweet Taste Receptor has Multiple
Potential Ligand Binding Sites Pp. 4591-4600
M. Cui, P. Jiang, E. Maillet, M. Max, R.F. Margolskee
and R. Osman
[Abstract]
Development of Quantitative Structure-Activity Relationships
and Its Application in Rational Drug Design Pp. 4601-4611
G.-F. Yang and X. Huang
[Abstract]
General Articles
The Psychopharmacology of European Herbs with Cognition-Enhancing
Properties Pp. 4613-4623
D.O. Kennedy and A.B. Scholey
[Abstract]
Altering the Sphingosine-1-Phosphate/Ceramide Balance:
A Promising Approach for Tumor Therapy Pp. 4625-4635
A. Huwiler and J. Pfeilschifter
[Abstract]
Vasoconstrictor Therapy for Hepatorenal Syndrome in
Liver Cirrhosis Pp. 4637-4647
L.E. Schmidt and H. Ring-Larsen
[Abstract]
Drug-Herb Interactions: Eliminating Toxicity with
Hard Drug Design Pp. 4649-4664
Xiao-Xia Yang, Ze-Ping Hu, Wei Duan, Yi-Zhun Zhu and Shu-Feng
Zhou
[Abstract]
Abstracts
[Back
to top]
Editorial: SARS-CoV: A Scenario of Modern Drug Design
Infection of viruses usually results in considerable mortality
and morbidity worldwide for our human beings. Such as notorious
HIV virus, it has imperiled the very fabric of human society
as no disease in human history has before. It is estimated
that deaths from this pandemic will rival those of the bubonic
plague, which killed 93 million people. Epidemic infection
of any other viruses has been always a deadly dream in human
history. Identified as a novel species of coronavirus, the
SARS-CoV has caused severe acute respiratory syndrome (SARS)
in late 2002 [1]. Air travel spread it rapidly around the
world, and ultimately this virus infected about 8000 people
and caused about 800 deaths in 26 countries on 5 continents
[2]. Aggressive quarantine measures have successfully terminated
the disease, and most likely the virus no longer circulates
in the human populations. On the other hand, the battle against
virus remains to be everlasting, and top scientists from around
the world are committed to develop antiviral drugs and vaccines.
At this side, scientists in China together with others involved
world-widely have contributed greatly to the latest advances
of the scientific studies on SARS-CoV from a number of subjects,
leading reasonable drug discovery and design targeting several
corresponding key proteins of SARS-CoV.
Using multiple strategies, from biochemical investigations
to computational simulations, works in the lab of Dr. Xu Shen
and Dr. Hualiang Jiang [3] have provided invaluable understanding
for the structural and functional characteristics of major
proteins responsible for the infection and replication of
SARS-CoV, thus vital for the rational drug development and
exploration of feasible therapy against this disease.
To understand the catalytic mechanism of SARS-CoV, Dr. Luhua
Lai [4] focused on the questions about the quaternary structures
and substrate selectivity of this target protein using a variety
of biophysical and biochemical methods. It is found that this
atypical enzyme also follows the general base catalytic mechanism,
and some positions at active site are found to be main determinants
for substrate specificity as revealed by HPLC assay on synthesized
peptides.
As performed by Dr. Yexue Li [5], the functional genomics
and molecular evolution studies on the SARS-CoV have also
found that four proteins were absolutely responsible for nosogenesis
of SARS, namely the spike (S) protein; small envelop (E) protien;
membrane (M) protein; and nuleocaspid (N) protein. It is also
demonstrated that SARS must be originated from wild animals,
and particularly the Spike gene, is essential for the transition
from animal-to-human transmission to human-to-human transmission.
Studies through structural crystallization on various aspects
of the main protease, as done in Dr. Zihe Rao’s lab
[6], have given fundamental insights for both the static and
dynamics properties of coronavirus Mpro and functional
assignment for different domains. Well-shaping on the catalytic
site and substrate binding pocket has laid solid ground for
further highly effective and selective inhibitor design against
CoV Mpro. It is hopefully to discover a single
agent with clinical potential through studies of enzyme activity
assay, high-throughput screening, virtual screening and ab
initio inhibitor design.
As typically done in the area of drug discovery and design,
Dr. Roman Osman [7] has performed combinatory computational
and biochemical studies on the sweet taste receptor. The reasonable
ligand binding sites are identified and verified by convincing
site-directed mutagenesis experiments. These studies have
led to a better understanding of the structure and function
of the sweet taste receptor, and are guiding the rational
structural-based design of novel sweeteners, of which could
be used in the treatment of human obesity and diabetes.
Starting from discovered lead compounds and analogs, Dr. Guangfu
Yang [8] provided a unique way of relating the structural
descriptors, especially derived from accurate quantum chemistry
calculations, with measurable bio-activities. These descriptors
cover the features of small molecules from steric, electronic
to hydrophobic properties et al., and have been testified
as an extension of traditional quantitative structure-activity
relationships, also being powerful tools in the design of
novel active compounds or positive modification of available
low-activity compounds.
Finally, I would like to give my sincere thanks to all the
authors for their great contributions to this issue mainly
focused on SARS-CoV and related advances in modern drug discovery,
particularly thanks to Dr. Xu Shen and Dr. Hualiang Jiang
for their kindly offering of the cover picture.
References
[1] van der Hoek L, Pyrc K, Jebbink MF, Vermeulen-Oost W,
Berkhout RJ, Wolthers KC, Wertheim-van Dillen PM, Kaandorp
J, Spaargaren J, Berkhout B. Identification of a new human
coronavirus. Nat Med 2004; 10(4): 368-373.
[2] Perlman S, Dandekar AA. Immunopathogenesis of coronavirus
infections: implications for SARS. Nature Rev Immunol 2005;
5(12): 917-927.
[3] Chen S, Luo H, Chen L, Chen J, Shen J, Zhu W, Chen K,
Shen X, Jiang H. An overall picture of SARS coronavirus (SARS-CoV)
genome-encoded major proteins: structures, functions and drug
development. Curr Pharm Des 2006; 12(35): 4539-4553.
[4] Lai L, Chen H, Wei P, Huang C, Liu S, Fan K, Zhou L, Han
X, Liu Z, Pei J, Liu Y. Quaternary structure, substrate selectivity
and inhibitor design for SARS 3C-like proteinase. Curr Pharm
Des 2006; 12(35): 4555-4564.
[5] Hao P, Chen M, Zhang G, He W, Li Y.Bioinformatics research
on the SARS coronavirus (SARS_CoV) in China. Curr Pharm Des
2006; 12(35): 4565-4572.
[6] Yang H, Bartlam M, Rao Z. Drug design targeting the main
protease, the Achilles' heel of coronaviruses. Curr Pharm
Des 2006; 12(35): 4573-4590.
[7] Cui M, Jiang P, Maillet E, Max M, Margolskee RF, Osman
R. The heterodimeric sweet taste receptor has multiple potential
ligand binding sites. Curr Pharm Des 2006; 12(35): 4591-4600.
[8] Yang G-F, Huang X. Development of quantitative structure-activity
relationships and applications in rational drug design. Curr
Pharm Des 2006; 12(35): 4601-4611.
Xiaoqin Huang, Ph.D.
College of Pharmacy
University of Kentucky
741 South Limestone Street
Lexington, KY 40536
USA
[Back to top]
An Overall Picture of SARS Coronavirus (SARS-CoV)
Genome-Encoded Major Proteins: Structures, Functions and Drug
Development
S. Chen, H. Luo, L. Chen, J. Chen, J. Shen, W. Zhu, K.
Chen, X. Shen and H. Jiang
A severe atypical pneumonia designated as severe acute respiratory
syndrome (SARS) by The World Health Organization broke out
in China and menaced to more than other 30 countries between
the end of the year 2002 and June of the year 2003. A novel
coronavirus called severe acute respiratory syndrome coronavirus
(SARS-CoV) has been recently identified as the etiological
agent responsible for the infectious SARS disease. Based on
extensively scientific cooperation and almost two-year’s
studies, remarkable achievements have been made in the understanding
of the phylogenetic property and the genome organization of
SARS-CoV, as well as the detailed characters of the major
proteins involved in SARS-CoV life cycle. In this review,
we would like to summarize the substantial scientific progress
that has been made towards the structural and functional aspects
of SARS-CoV associated key proteins. The progress focused
on the corresponding key proteins’ structure-based drug
and vaccine developments has been also highlighted. The concerted
and cooperative response for the treatment of the SARS disease
has been proved to be a triumph of global public health and
provides a new paradigm for the detection and control of future
emerging infectious disease threats.
[Back to top]
Quaternary Structure, Substrate Selectivity and Inhibitor
Design for SARS 3C-Like Proteinase
L. Lai, H. Chen, P. Wei, C. Huang, S. Liu, K. Fan, L.
Zhou, X. Han, Z.Liu, J. Pei and Y. Liu
The SARS coronavirus 3C-like proteinase is recognized as a
potential drug design target for the treatment of severe acute
respiratory syndrome. In the past few years, much work has
been done to understand the catalytic mechanism of this target
protein and to design its selective inhibitors. The protein
exists as a dimer/monomer mixture in solution and the dimer
was confirmed to be the active species for the enzyme reaction.
Quantitative dissociation constants have been reported for
the dimer by using analytic ultracentrifuge, gel filtration
and enzyme assays. Though the enzyme is a cysteine protease
with a chymotrypsin fold, SARS 3C-like proteinase follows
the general base catalytic mechanism similar to chymotrypsin.
As the enzyme can cut eleven different sites on the viral
polyprotein, the substrate specificity has been studied by
synthesized peptides corresponding or similar to the cleavage
sites on the polyprotein. Predictive model was built for substrate
structure and activity relationships and can be applied in
inhibitor design. Due to the lack of potential drugs for the
treatment of SARS, the discovery of inhibitors against SARS
3C-like proteinase, which can potentially be optimized as
drugs appears to be highly desirable. Various groups have
been working on inhibitor discovery by virtual screening,
compound library screening, modification of existing compounds
or natural products. High-throughput in vitro assays,
auto-cleavage assays and viral replication assays have been
developed for inhibition activity tests. Inhibitors with IC50
values as low as 60 nM have been reported.
[Back to top]
Bioinformatics Research on the SARS Coronavirus (SARS_CoV)
in China
P. Hao, M. Chen, G. Zhang, W. He and Y. Li
Severe acute respiratory syndrome (SARS) first appeared in
2002 in China, which fastly affected about 8000 patients over
29 countries and caused 774 fatalities. As its pathogen was
identified as a new kind of coronavirus (SARS_CoV), its genome
was quickly sequenced on several isolates. Studies on its
functional genomics were performed by combinatorial application
of all the available bioinformatics tools and the development
of new programs. In this way, it was found that the four proteins
were absolutely responsible for nosogenesis of SARS, i.e.
spike (S) protein; small envelop (E) protein; membrane (M)
protein; and nucleocaspid (N) protein. Molecular evolution
studies have revealed that SARS must be originated from wild
animals, and it was demonstrated that the major genetic variations
in some critical genes, particularly the Spike gene, was essential
for the transition from animal-to-human transmission to human-to-human
transmission. Theoretical models, either Logistic model or
SIR model, were developed to describe the transmission of
SARS. The recorded difference of SARS spreading in Beijing
and Hong Kong was also reasonably analyzed according to these
models. The whole process of fruitful bioinformatics studies,
along with other related scientific investigations have set
up an unprecedented paradigm for human of how to battle against
sudden-breaking and catastrophic epidemics.
[Back to top]
Drug Design Targeting the Main Protease, the Achilles'
Heel of Coronaviruses
H. Yang, M. Bartlam and Z. Rao
Coronaviruses (CoVs), a genus containing about 26 known species
to date, cause highly prevalent diseases and are often severe
or fatal in humans and animals. In 2003, a previously unknown
coronavirus was identified to be the etiological agent of
a global outbreak of a form of life-threatening pneumonia
called severe acute respiratory syndrome (SARS). No efficacious
therapy is currently available, and vaccines and drugs are
under development to prevent SARS-CoV infection in many countries.
The CoV main protease (Mpro), which plays a pivotal
role in viral gene expression and replication through a highly
complex cascade involving the proteolytic processing of replicase
polyproteins, is an attractive target for drug design. This
review summarizes the recent advances in biological and structural
studies, together with development of inhibitors targeting
CoV Mpros. It is expected that inhibitors targeting
CoV Mpros could be developed into wide-spectrum
antiviral drugs against existing and possible future emerging
CoV-associated diseases.
[Back to top]
The Heterodimeric Sweet Taste Receptor has Multiple
Potential Ligand Binding Sites
M. Cui, P. Jiang, E. Maillet, M. Max, R.F. Margolskee
and R. Osman
The sweet taste receptor is a heterodimer of two G protein
coupled receptors, T1R2 and T1R3. This discovery has increased
our understanding at the molecular level of the mechanisms
underlying sweet taste. Previous experimental studies using
sweet receptor chimeras and mutants show that there are at
least three potential binding sites in this heterodimeric
receptor. Receptor activity toward the artificial sweeteners
aspartame and neotame depends on residues in the amino terminal
domain of human T1R2. In contrast, receptor activity toward
the sweetener cyclamate and the sweet taste inhibitor lactisole
depends on residues within the transmembrane domain of human
T1R3. Furthermore, receptor activity toward the sweet protein
brazzein depends on the cysteine rich domain of human T1R3.
Although crystal structures are not available for the sweet
taste receptor, useful homology models can be developed based
on appropriate templates. The amino terminal domain, cysteine
rich domain and transmembrane helix domain of T1R2 and T1R3
have been modeled based on the crystal structures of metabotropic
glutamate receptor type 1, tumor necrosis factor receptor,
and bovine rhodopsin, respectively. We have used homology
models of the sweet taste receptors, molecular docking of
sweet ligands to the receptors, and site-directed mutagenesis
of the receptors to identify potential ligand binding sites
of the sweet taste receptor. These studies have led to a better
understanding of the structure and function of this heterodimeric
receptor, and can act as a guide for rational structure-based
design of novel non-caloric sweeteners, which can be used
in the fighting against obesity and diabetes.
[Back to top]
Development of Quantitative Structure-Activity Relationships
and Its Application in Rational Drug Design
G.-F. Yang and X. Huang
Over forty years have elapsed since Hansch and Fujita published
their pioneering work of quantitative structure-activity relationships
(QSAR). Following the introduction of Comparative Molecular
Field Analysis (CoMFA) by Cramer in 1998, other three-dimensional
QSAR methods have been developed. Currently, combination of
classical QSAR and other computational techniques at three-dimensional
level is of greatest interest and generally used in the process
of modern drug discovery and design. During the last several
decades, a number of different mythologies incorporating a
range of molecular descriptors and different statistical regression
ways have been proposed and successfully applied in developing
of new drugs, thus QSAR method has been proven to be indispensable
in not only the reliable prediction of specific properties
of new compounds, but also the help to elucidate the possible
molecular mechanism of the receptor-ligand interactions. Here,
we review the recent developments in QSAR and their applications
in rational drug design, focusing on the reasonable selection
of novel molecular descriptors and the construction of predictive
QSAR models by the help of advanced computational techniques.
[Back to top]
The Psychopharmacology of European Herbs with Cognition-Enhancing
Properties
D.O. Kennedy and A.B. Scholey
Extensive research suggests that a number of plant-derived
chemicals and traditional Oriental herbal remedies possess
cognition-enhancing properties. Widely used current treatments
for dementia include extracts of Ginkgo biloba and
several alkaloidal, and therefore toxic, plant-derived cholinergic
agents.
Several non-toxic, European herbal species have pan-cultural
traditions as treatments for cognitive deficits, including
those associated with ageing. To date they have not received
research interest commensurate with their potential utility.
Particularly promising candidate species include sage (Salvia
lavandulaefolia/officinalis), Lemon balm (Melissa
officinalis) and rosemary (Rosmarinus officinalis).
In the case of sage, extracts possess anti-oxidant, estrogenic,
and anti-inflammatory properties, and specifically inhibit
butyryl- and acetyl-cholinesterase. Acute administration has
also been found to reliably improve mnemonic performance in
healthy young and elderly cohorts, whilst a chronic regime
has been shown to attenuate cognitive declines in sufferers
from Alzheimer's disease.
In the case of Melissa officinalis, extracts have,
most notably, been shown to bind directly to both nicotinic
and muscarinic receptors in human brain tissue. This property
has been shown to vary with extraction method and strain.
Robust anxiolytic effects have also been demonstrated following
acute administration to healthy humans, with mnemonic enhancement
restricted to an extract with high cholinergic binding properties.
Chronic regimes of aromatherapy and essential oil respectively
have also been shown to reduce agitation and attenuate cognitive
declines in sufferers from dementia.
Given the side effect profile of prescribed cholinesterase
inhibitors, and a current lack of a well tolerated nicotinic
receptor agonist, these herbal treatments may well provide
effective and well-tolerated treatments for dementia, either
alone, in combination, or as an adjunct to conventional treatments.
[Back to top]
Altering the Sphingosine-1-Phosphate/Ceramide Balance:
A Promising Approach for Tumor Therapy
A. Huwiler and J. Pfeilschifter
In recent years sphingolipids have emerged as important signaling
molecules regulating fundamental cell responses such as cell
death and differentiation, proliferation and aspects of inflammation.
Especially ceramide has been a main focus of research since
it possesses pro-apoptotic capacity in many cell types. A
counterplayer of ceramide was found in sphingosine-1-phosphate
(S1P), which is generated from ceramide by the consecutive
actions of ceramidase and sphingosine kinase. S1P can potently
induce cell proliferation via binding to and activation
of the Edg family of receptors which have now been renamed
as S1P receptors. Obviously, a delicate balance between ceramide
and sphingosine-1-phosphate determines whether cells undergo
apoptosis or proliferate, two cell responses that are critically
involved in tumor development. Directing the balance in favor
of ceramide, i.e. by inhibiting ceramidase or sphingosine
kinase activities may support the pro-apoptotic action of
ceramide and thus may have beneficial effects in cancer therapy.
This review will summarize novel insights into the regulation
of sphingolipid formation and their potential involvement
in tumor development. Finally, we will pinpoint potential
new targets for tumor therapy.
[Back to top]
Vasoconstrictor Therapy for Hepatorenal Syndrome in
Liver Cirrhosis
L.E. Schmidt and H. Ring-Larsen
Hepatorenal syndrome is a severe, but not uncommon complication
of decompensated liver cirrhosis. In particular, the rapidly
progressive form of hepatorenal syndrome (type 1) is associated
with a dismal prognosis. Established hepatorenal syndrome
has a spontaneous reversibility below 5%. Hepatorenal syndrome
is involved in more than 50% of cirrhosis-related mortality.
Thus, any treatment capable of reversing hepatorenal syndrome
would be expected to reduce morbidity and mortality from liver
cirrhosis.
A pathophysiological hallmark of hepatorenal syndrome is arterial
underfilling due to an extreme splanchnic vasodilatation.
Consequently, potent vasoconstrictors capable of reversing
this vasodilatation have been investigated in hepatorenal
syndrome.
Several vasoconstrictors including the α-adrenergic
agonists, midodrine and noradrenalin, and the vasopressor
analogues, ornipressin and terlipressin, have all been associated
with a significant improvement in renal function in 57 to
100% of cases and even reversal of hepatorenal syndrome in
42 to 100% of cases. The majority of recent studies are on
terlipressin. A randomized, controlled trial showed a significant
effect of terlipressin on reversal of hepatorenal syndrome.
The contribution of volume expansion to the beneficial effects
of vasoconstrictors on hepatorenal syndrome remains to be
determined.
In general, reversal of hepatorenal syndrome was associated
with an improved survival. However, it remains to be determined
if vasoconstrictor therapy should be used in hepatorenal syndrome
in general, or if it should be reserved for potential candidates
for liver transplantation.
In conclusion, evidence for a beneficial effect of vasoconstrictor
therapy for the treatment of hepatorenal syndrome is steadily
accumulating. Confirmation of the preliminary data in larger
randomized, controlled trials looking at long-term survival
is required.
[Back to top]
Drug-Herb Interactions: Eliminating Toxicity with
Hard Drug Design
Xiao-Xia Yang, Ze-Ping Hu, Wei Duan, Yi-Zhun Zhu and Shu-Feng
Zhou
By searching the literatures, it was found that a
total of 32 drugs interacting with herbal medicines in humans.
These drugs mainly include anticoagulants (warfarin, aspirin
and phenprocoumon), sedatives and antidepressants (midazolam,
alprazolam and amitriptyline), oral contraceptives, anti-HIV
agents (indinavir, ritonavir and saquinavir), cardiovascular
drug (digoxin), immunosuppressants (cyclosporine and tacrolimus)
and anticancer drugs (imatinib and irinotecan). Most of them
are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein
(PgP) and many of which have narrow therapeutic indices. However,
several drugs including acetaminophen, carbamazepine, mycophenolic
acid, and pravastatin did not interact with herbs. Both pharmacokinetic
(e.g. induction of hepatic CYPs and intestinal PgP) and/or
pharmacodynamic mechanisms (e.g. synergistic or antagonistic
interaction on the same drug target) may be involved in drug-herb
interactions, leading of altered drug clearance, response
and toxicity. Toxicity arising from drug-herb interac-tions
may be minor, moderate, or even fatal, depending on a number
of factors associated with the patients, herbs and drugs.
Predicting drug-herb interactions, timely identification of
drugs that interact with herbs, and therapeutic drug moni-toring
may minimize toxic drug-herb interactions. It is likely to
predict pharmacokinetic herb-drug interactions by following
the pharmacokinetic principles and using proper models that
are used for predicting drug-drug interactions. Identification
of drugs that interact with herbs can be incorporated into
the early stages of drug development. A fourth approach for
circumventing toxicity arising from drug-herb interactions
is proper design of drugs with minimal potential for herbal
interaction. So-called “hard drugs” that are not
metabolized by CYPs and not transported by PgP are believed
not to interact with herbs due to their unique pharmacokinetic
properties. More studies are needed and new approached are
required to minimize toxicity arising from drug-herb interactions.
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