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Current Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 4, Number 3, October 2007
Contents
Predictive QSAR Modeling for the Successful Predictions
of the ADMET Properties of Candidate Drug Molecules
Pp. 141-149
Mahmud Tareq Hassan Khan and Ingebrigt Sylte
[Abstract]
Computational Analysis of Adhesion of Primer Ligands
to Dentinal Collagen: Effect of Spacer Groups in Ligand and
Amino Acid Residue Sequence Differences in Collagen
Pp. 150-161
J. Vaidyanathan, S. Ravichandran and T.K. Vaidyanathan
[Abstract]
Biologic Aspects of Thrombopoietin and the Development
of Novel Thrombopoietic Agents for Clinical Use Pp.
162-173
Maria Laura Evangelista, Sergio Amadori and Roberto Stasi
[Abstract]
Alternative Splice Variants of Survivin as Potential
Targets in Cancer Pp. 174-191
Janardhan Sampath and Louis M. Pelus
[Abstract]
Influence of Sulfobutylether-β-Cyclodextrin
on the Stability of S and R- Omeprazole Pp. 192-197
Snezana Agatonovic-Kustrin, Desmond Williams, Nader Ibrahim
and Beverley D. Glass
[Abstract]
Design and Synthesis of New N1 and C3-Substituted
4 Fluoroindolic Melatoninergics Pp. 198-207
Andrew Tsotinis, Andreas Eleutheriades, Kathryn Davidson
and David Sugden
[Abstract]
Molecular Approaches to Cervical Cancer Therapy Pp.
208-219
Luis M. Alvarez-Salas and Joseph A. DiPaolo
[Abstract]
Abstracts
[Back to top]
Predictive QSAR Modeling for the Successful Predictions of
the ADMET Properties of Candidate Drug Molecules
Mahmud Tareq Hassan Khan and Ingebrigt Sylte
Chemical breakthrough generates large numbers of prospective
drug molecules; the use of ADMET (absorption, distribution,
metabolism, excretion and toxicity) properties is flattering
progressively more imperative in the drug discovery, assortment,
development and promotion processes. Due to the inauspicious
ADMET properties a huge amount of molecules in the development
stage got failure. In the past years several authors reported
that it possible to do some prediction of the ADMET properties
using the structural features of the molecules, suing several
approaches. One of the most important approaches is QSAR modeling
of the data derived from their activity profiles and their
different structural features (i.e., quantitative
molecular descriptors). This review is critically assessing
some of the most important issues for the effective prediction
of ADMET properties of drug candidates based on QSAR modeling
approaches.
[Back to top]
Computational Analysis of Adhesion of Primer Ligands
to Dentinal Collagen: Effect of Spacer Groups in Ligand and
Amino Acid Residue Sequence Differences in Collagen
J. Vaidyanathan, S. Ravichandran and T.K. Vaidyanathan
This study sought to assess by computer modeling the interactions
between dentinal collagen and primer monomer ligands used
to promote bonding of restorations to tooth. Modeling was
carried out both by direct and indirect methods to probe interaction
mechanisms. Ligands studied in this investigation conformed
chemically to methacrylate phosphates of alkane diol, with
changes in the number of methylene spacer groups. Increase
in number of methylene groups in the series introduces increasing
levels of ligand conformational freedom. An automatic docking
program was used to analyze the effect of these changes on
primer-collagen interactions in direct (target-based) modeling.
The effect of limited modifications of amino acid residue
sequences in structural variants of type 1 dentinal collagen
was also assessed in this approach. The indirect (ligand-based)
modeling used a pharmacaphore search to mimic primer binding
to type 1 collagen using a common functional alignment algorithm.
Docking energy, and the non-bonded and electrostatic contributions
to it, showed statistically highly significant differences
(p<0.0001) with ligand conformational freedom. But the
effect of collagen composition differences was, although statistically
significant (p<0.05), relatively small. Both target-based
direct docking and ligand-based indirect modeling visualizations
showed that conformations tended to align in a 3-D geometric
pattern in bound states, and that the conformational flexibility
of the ligands played a critical role in alignment. The results
suggest that incorporation of spacer groups in primer monomers
may modify dentin bonding to improve overall adhesion under
optimum conditions.
[Back to top]
Biologic Aspects of Thrombopoietin and the Development
of Novel Thrombopoietic Agents for Clinical Use
Maria Laura Evangelista, Sergio Amadori and Roberto Stasi
Thrombocytopenia is a frequent finding in several clinical
settings, including bone marrow failure associated with various
disorders, immune-mediated thrombocytopenia, and chronic liver
diseases. Currently, there is an unmet need for thrombopoietic
agents to treat this condition.
Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis,
and is the endogenous ligand for the thrombopoietin receptor
that is expressed on the surface of megakaryocytes and megakaryocytic
precursors.
Although clinical trials with first generation thrombopoietic
agents were abruptly discontinued after the development of
TPO autoantibodies had been observed, non-antigenic second
generation thrombopoietic growth factors with unique pharmacological
properties have been developed. These include TPO peptide
mimetics (AMG 531 and Fab59), TPO non-peptide mimetics (eltrombopag,
NIP-004, and AKR-501) and TPO agonist antibodies. All of these
bind to and activate the TPO receptor in different ways but
all via JAK2/STAT signalling pathways, producing
a dose-dependent rise in platelet counts. In view of their
use as therapeutic agents, nonpeptide agonists seem to have
an advantage over peptide agonists, in that they could be
orally bioavailable.
The aim of the present review is to illustrate the biology
of TPO and its receptor, and to describe the structure and
function of the new thrombopoietic agents.
[Back to top]
Alternative Splice Variants of Survivin as Potential
Targets in Cancer
Janardhan Sampath and Louis M. Pelus
Survivin, a member of the IAP family is an attractive target
for cancer treatment due to it’s over expression in
most cancers and low or no expression in most differentiated
adult tissues. Survivin expression is a poor prognostic marker
in a number of cancers. Clinical trials are currently underway
evaluating anti-sense oligonucleotides against Survivin, immunotherapy
using Survivin primed dentritic cells and peptide mimics that
block interaction of Survivin with Hsp90 resulting in loss
of Survivin protein stability. Additional approaches using
ribozymes against Survivin mRNA, or dominant-negative cDNA
to block Survivin function are in pre-clinical stages. Like
many genes, Survivin is alternately spliced and a number of
new splice variants have recently been identified. Expression
of some of these splice variants correlates with loss of steroid
receptors as well as the tumor suppressor p53, in some cancers,
suggesting that like wild-type Survivin, at least some of
these splice variants may also have prognostic relevance.
This review will focus on the current understanding of the
function of Survivin splice variants and their expression
and sub-cellular localization in normal and neoplastic tissues
as well as critically evaluating the potential toxicity of
the Survivin directed therapies and their predicted effect
on the alternatively spliced Survivin isoforms.
[Back to top]
Influence of Sulfobutylether-β-Cyclodextrin
on the Stability of S and R- Omeprazole
Snezana Agatonovic-Kustrin, Desmond Williams, Nader Ibrahim
and Beverley D. Glass
Omeprazole (OME), a proton pump inhibitor used to treat acid
reflux disease and gastric ulcers presents a formulation challenge
due to its rapid decomposition at acidic and neutral pHs.
Thus, the aim of this project was to investigate whether interaction
with sulfobutylether-β-cyclodextrin
(Captisol®-CD)
could improve omeprazole stability and provide more efficient
oral liquid formulations.
A stability-indicating high performance liquid chromatography
assay allowed for the quantitation of S- and R-forms of OME
in the presence and absence of Captisol®-CD.
The developed method was validated to discriminate between
OME and its degradation products and used to describe the
kinetic model of OME at different pH values over a period
of 36 days.
Calculated degradation constants (kobs),
were directly correlated with the H+
concentrations of the solutions regardless of whether the
omeprazole was complexed with the Captisol®-CD
or not. Moreover, the pH-rate profile curve indicated that
in all cases, maximum stability was achieved at pH 11. Though
it was anticipated that interaction of OME with Captisol®-CD
might increase the relative stability of OME at a lower pH,
the cavity of the cyclodextrin was too small to allow the
inclusion to occur. However the R-isomer of OME, both in the
presence or absence of the cyclodextrin appeared to be slightly
less stable than the corresponding S-form at the same pH conditions.
[Back to top]
Design and Synthesis of New N1 and C3-Substituted
4 Fluoroindolic Melatoninergics
Andrew Tsotinis, Andreas Eleutheriades, Kathryn Davidson
and David Sugden
A series of new C-3 and N1-substituted 4-fluorotryptamides
have been prepared and tested for their ability to activate
pigment granule aggregation in Xenopus laevis melanophores
and bind to the recombinant human MT1
and MT2 melatonin receptor
subtypes expressed in NIH 3T3 cells. Planar sp2
geometry at C-3-βC
seems to decrease the population of the preferred conformation
as it renders 4-fluoroindoles 4b-d weaker
antagonists than their C-3-βC-unsubstituted
congeners 3a-e. This effect is not preclusively
linked with the C-3 region, as the same geometry around N1
(compounds 5a-c) similarly leads to weak
antagonistic action. Last, the new C-3 substituted 4-fluorotryptamides
presented herein are substantially more potent than their
respective N-OMe functionalized congeners, previously
reported.
[Back to top]
Molecular Approaches to Cervical Cancer Therapy
Luis M. Alvarez-Salas and Joseph A. DiPaolo
Cervical cancer is the second most common malignancy
in women worldwide. Two HPV strains, HPV-16 and 18, occur
in the 70% of untreated cancers. Expression of viral oncogenes
E6 and E7 disrupt the cell cycle by interfering with p53 and
p107Rb. It is known that
HPV infection is necessary but insufficient to cause malignancy.
Furthermore, persistence of HPV-16 or 18 in women does not
necessarily result in cancer. Persistence indicates the importance
of other factors for malignant conversion of high-grade HPV
infection. The multi-step cervical carcinogenesis process
is amendable to molecular therapeutics such as therapeutic
nucleic acids (TNAs). TNA-based therapies for cervical carcinoma
include ribozymes, antisense oligonucleotides (AS-ODNs) and
small interfering RNAs (siRNAs). In vitro experiments
with TNAs successfully inhibited E6/E7 expression and caused
induction of apoptosis and/or senescence in cervical carcinoma
cells. Early ribozyme and AS-ODN approaches showed promise
as therapeutic moieties for cervical cancer. Despite the very
high in vitro efficiency of siRNA-based therapies
they present the same issues that burdened clinical development
of ribozymes and AS-ODNs. These issues include intracellular
target accessibility, specificity and delivery. Ribozymes
are useful for functional genomic studies including diagnosis.
Moreover, AS-ODNs appear better suited for clinical protocols
because recent advances in nucleic acid chemistry allow higher
cell uptake with very low off-target effects leading to actual
AS-ODNs clinical applications. By using combined treatments
with multiple targets it will be possible to apply TNAs directly
to the cancerous cervix to destroy viral RNA and obliterate
the tumor.
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