| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 16, 2008
Contents
Modelling and Informatics in the Analysis of P.
falciparum DHFR Enzyme Inhibitors Pp. 1552-1569
Legesse Adane and Prasad V. Bharatam
[Abstract]
Structure –Activity Relationships of PDE5
Inhibitors Pp. 1570-1585
D. Eros, Cs. Szántai-Kis, R. Kiss, Gy. Kéri,
B. Hegymegi-Barakonyi, I. Kövesdi and L. Orfi
[Abstract]
Molecular Mechanisms of Anti-Inflammatory Activity
Mediated by Flavonoids Pp. 1586-1605
Ana Gomes, Eduarda Fernandes, José L.F.C.
Lima, Lurdes Mira and M. Luísa Corvo
[Abstract]
Catalytic Activity of Certain Antibodies as a Potential Tool
for Drug Synthesis and for Directed Prodrug Therapies
Pp. 1606-1615
T. Wójcik and K. Kiec-Kononowicz
[Abstract]
Chemistry and Bioactivity of Flos Magnoliae,
A Chinese Herb for Rhinitis and Sinusitisb Pp. 1616-1627
Y. Shen, C.G. Li, S.F. Zhou, E.C.K. Pang,
D.F. Story and C.C.L. Xue
[Abstract]
New Therapeutic Approaches to Liver Fibrosis:
A Practicable Route? Pp. 1628-1644
Zardi Enrico M., Dobrina Aldo, Ambrosino Giovanni,
Margiotta Domenico, Polistina Francesco and Afeltra
Antonella
[Abstract]
A Slit in Podocyte Death Pp. 1645-1654
Juan Antonio Moreno, Maria Dolores Sanchez-Niño,
Ana Belen Sanz, Markus Lassila, Harry Holthofer, Luis Miguel
Blanco-Colio, Jesus Egido, Marta Ruiz-Ortega and Alberto
Ortiz
[Abstract]
Abstracts
[Back to top]
Modelling and Informatics in the Analysis
of P. falciparum DHFR
Enzyme Inhibitors
Legesse Adane and Prasad V. Bharatam
Malaria is one of the most prevalent diseases of our
planet which claims millions of lives annually. Plasmodium
falciparum is the causative agent of majority of the
mortality and morbidity associated with malaria particularly
in tropical countries. Resistance of the parasite to the currently
available chemotherapeutic agents poses a serious threat to
human being. Inhibition of P. falciparum dihydrofolate
reductase (DHFR) enzyme has been used as one of the strategies
in curbing malaria. However, due to mutation in the active-site
of the enzyme particularly at 16, 51, 59, 108, and 164 residues,
the parasite developed resistance to most of antifolate drugs
such as cycloguanil and pyrimethamine. Thus, design of new
and potent antimalarial agents which are effective against
both wild-type and mutant enzymes is very essential in order
to minimize burden of P. falciparum malaria.
Computer-aided drug design approaches are playing a crucial
role in the design of potential antimalarial drug candidates.
In this article, molecular modelling studies based on docking,
pharmacophore mapping, QSAR, homology modelling, and quantum
chemical studies are reviewed. The importance of these methods
in understanding mechanism of drug resistance at a molecular
level, and design of antimalarial drug candidates are discussed
briefly. The examples mentioned in the review could give insights
into the wide range of possibilities of using computer–aided
drug design (CADD) methodologies.
[Back to top]
Structure –Activity Relationships of PDE5 Inhibitors
D. Eros, Cs. Szántai-Kis, R. Kiss, Gy. Kéri,
B. Hegymegi-Barakonyi, I. Kövesdi and L. Orfi
cGMP has a short-term effect on smooth muscle tone and
a longer-term effect on responses to chronic drug treatment
or proliferative signals. cGMP-Phosphodiesterase type 5 (PDE5)
hydrolizes cGMP, and the result is smooth muscle contraction.
PDE5 is a relatively novel therapeutic target of various diseases,
such as erectile dysfunction and pulmonary hypertension. The
most intensively examined and marketed PDE5 inhibitor was
sildenafil (Viagra) but recently vardenafil (Levitra) and
tadalafil (Cialis) were launched with beneficial ADME parameters
and PDE5 selectivity. The increasing interest in PDE5 inhibition
made it reasonable to collect the available inhibitory data
from the scientific literature and set up a structure-activity
relationship study. Chemical structures of 438 compounds and
their cGMP-PDE5 inhibitory data (IC50)
were collected from recently published articles. In this paper
physiology, regulation and inhibition of PDE5 (and briefly
other PDE-s) are discussed and inhibitors are tabulated by
the core structures. Finally, a general QSAR model built from
these data is presented. All data used in the QSAR study were
summarized in a Supplement (for description please see the
online version of the article).
[Back to top]
Molecular Mechanisms of Anti-Inflammatory Activity
Mediated by Flavonoids
Ana Gomes, Eduarda Fernandes, José L.F.C.
Lima, Lurdes Mira and M. Luísa Corvo
Flavonoids (or bioflavonoids) are naturally occurring compounds,
ubiquitous in all vascular plants. These compounds have been
considered to possess anti-inflammatory properties, both
in vitro and in vivo. Although not fully understood,
these health-promoting effects have been mainly related to
their interactions with several key enzymes, signaling cascades
involving cytokines and regulatory transcription factors,
and antioxidant systems. The biological effects of flavonoids
will depend not only on these pharmacodynamic features but
also on their pharmacokinetics, which are dependent on their
chemical structure, administered dose schedule and route of
administration. Thus, the therapeutic outcome mediated by
flavonoids will result from a complex and interactive network
of effects, whose prediction require a deep and integrated
knowledge of those pharmacokinetic and pharmacodynamic factors.
The aim of the present review is thus to provide an integrated
update on the bioavailability and biotransformation of flavonoids
and the mechanisms of activity at the molecular, cellular,
organ and organism levels that may contribute to their anti-inflammatory
effects.
[Back to top]
Catalytic Activity of Certain Antibodies as a Potential Tool
for Drug Synthesis and for Directed Prodrug Therapies
T. Wójcik and K. Kiec-Kononowicz
Catalytic activity of certain antibodies was proposed by Linus
Pauling for the very first time more than six decades ago.
Since then few examples of catalytic antibodies (abzymes)
were found in human organism. From late 80’s many synthetic
abzymes were obtained after immunization by Transition State
Analogs (TSA). Another approach is based on functional mimicry
of antibody to an active site of an enzyme. Detection of an
abzymatic activity requires special immunoassays. This unique
strategy can be employed for new methods of drug synthesis,
as well as for in vivo therapies. Catalytic antibodies
seem to be a promising tool for therapeutic purposes, because
of their specifity and stereoselectivity.
[Back to top]
Chemistry and Bioactivity of Flos Magnoliae,
A Chinese Herb for Rhinitis and Sinusitis
Y. Shen, C.G. Li, S.F. Zhou, E.C.K. Pang,
D.F. Story and C.C.L. Xue
Flos Magnoliae (FM, Chinese name: Xin-yi) is one
of the most commonly used Chinese medicinal herbs. It has
a long history of clinical use for managing rhinitis, sinusitis
and headache. More than 20 different FM species have been
used clinically, which makes species identification and evaluation
of pharmacological effects of individual chemical ingredients
difficult. In this review, we have summarized the current
knowledge on FM phytochemistry and its bioactivity activities.
The bioactive compounds in FM include both lipid and water-soluble
components. More than 90% of the essential components of FM
species are terpenoids, including monoterpenes and sesquiterpenes.
Lignans and neolignans including tetrahydrofurofuran, tetrahydrofuran
and aryltetralin are also present in FM species. A small number
of water-soluble compounds have been isolated from Magnolia
flower buds, including a benzylisoquinoline alkaloid magnoflorine,
an ester ethyl-E-p-hydroxyl-cinnamate and a flavonoid
biondnoid. A wide range of pharmacological actions of FM have
been reported, including anti-allergy, anti-inflammation and
anti-microbial activity. The structure-activity relationship
analysis revealed the influence of methylation at position
5 on the 3,7-dioxabicyclo-(3,3,0)-octane backbone of six lignans
in antagonistic activities against platelet-activating factor.
In addition, the trans stereoisomer fargesin had
a much lower bioactivity than the cis stereoisomer
demethoxyaschantin. Recent studies have been directed towards
the isolation of other bioactive compounds. Further studies
on FM may help to develop new anti-inflammatory and anti-allergic
drugs.
[Back to top]
New Therapeutic Approaches to Liver Fibrosis: A Practicable
Route?
Zardi Enrico M., Dobrina Aldo, Ambrosino Giovanni,
Margiotta Domenico, Polistina Francesco and Afeltra
Antonella
The progress of research on the molecular pathogenesis of
liver fibrosis and the consequent discoveries are likely to
open new possibilities for therapeutic approaches to the management
of this disease in the future.
A key step towards this goal is a deeper comprehension of
both the complex molecular and cellular mechanisms and the
signaling involved in the development of hepatic fibrosis.
It is not yet clear, in fact, what role apoptosis, cytokines,
oxidants and other molecules play and what relationships exist
between them in favouring or delaying the onset of these adverse
mechanisms.
At present, a unique mechanism is recognized to be the main
reason for the cause and development of liver fibrosis: sustained
hepatic stellate cell activation and transformation. Therefore,
in this review, after considering the cause, development of
fibrosis and interrelation between molecular and cellular
profibrotic mechanisms, the part played in counteracting both
of these actions by some anti-oxidants and anti-fibrotic molecules
such as cytokines, prostacyclin and others will be taken into
consideration.
The gene therapy and the possible therapeutic use of liver
stem cells and tissue engineering will also be dealt with
briefly.
At the moment, however, the efficacy of these novel strategies
still needs to be further validated in animal studies and
confirmed in clinical trials. Some data that are already available
from in vitro and animal studies demonstrating the
effectiveness of novel approaches to inhibiting or treating
liver fibrosis can only offer moderate hope.
[Back to top]
A Slit in Podocyte Death
Juan Antonio Moreno, Maria Dolores Sanchez-Niño,
Ana Belen Sanz, Markus Lassila, Harry Holthofer, Luis Miguel
Blanco-Colio, Jesus Egido, Marta Ruiz-Ortega and Alberto
Ortiz
Recent advances have identified the podocyte as a key
target in glomerular injury. The podocyte is a highly specialized
cell which is responsible for the glomerular permselectivity
for proteins in the kidney. Podocyte injury or loss leads
to proteinuria. Apoptosis has been shown to contribute to
renal cell loss, including loss of podocytes. The most striking
feature of the podocyte is its ability to form intricate specialized
cell junctions, the slit diaphragm. Slit diaphragm proteins
play an important role in podocyte biology, protein permselectivity,
cell signalling and disease. This review focuses on recent
advances on the understanding of podocyte survival regulation,
its relationship to slit diaphragm structure and function,
and how this knowledge may affect our therapeutic approach
to proteinuric kidney disease.
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