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Current Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 3, Number 1, March 2006
Contents
Development and Validation of an In Silico
P450 Profiler Based on Pharmacophore Models Pp. 1-48
Daniela Schuster, Christian Laggner, Theodora M. Steindl and
Thierry Langer
[Abstract]
Rational Design Approaches to Chemical Libraries for
Hit Identification Pp. 49-65
Konstantin V. Balakin, Alexander V. Kozintsev, Alex S.
Kiselyov and Nikolay P. Savchuk
[Abstract]
Anti-Inflammatory and Anti-Oxidant Activity of a New
Class of Phenyl-Pyrazolone Derivatives Pp. 67-73
C. Cusan, G. Altinier, S. Sosa, F. Sibilla, F. Bucar,
A. Tubaro, M. Prato, G. Spalluto and T. Da Ros
[Abstract]
Fine-Grained Statistical Torsion Angle Potentials
are Effective in Discriminating Native Protein Structures
Pp. 75-81
Alessandro Albiero and Silvio C.E. Tosatto
[Abstract]
Advanced Glycation End Products (AGEs) and their Receptor
(RAGE) System in Diabetic Retinopathy Pp. 83-88
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori
Matsui
[Abstract]
Abstracts
[Back to top]
Development and Validation of an In Silico
P450 Profiler Based on Pharmacophore Models
Daniela Schuster, Christian Laggner, Theodora M. Steindl and
Thierry Langer
In today’s drug discovery process, the very early consideration
of ADME properties is aimed at a reduction of drug candidate
drop out rate in later development stages. Apart from in
vitro testing, in silico methods are evaluated as complementary
screening tools for compounds with unfavorable ADME attributes.
Especially members of the cytochrome P450 (P450) enzyme superfamily
- e.g. P450 1A2, P450 2C9, P450 2C19, P450 2D6, and P450 3A4
- contribute to xenobiotic metabolism, and compound interaction
with one of these enzymes is therefore critically evaluated.
Pharmacophore models are widely used to identify common features
amongst ligands for any target. In this study, both structure-based
and ligand-based models for prominent drug-metabolizing members
of the P450 family were generated employing the software packages
LigandScout and Catalyst. Essential chemical ligand features
for substrate and inhibitor activity for all five P450 enzymes
investigated were determined and analyzed. Finally, a collection
of 11 pharmacophores for substrates and inhibitors was evaluated
as an in silico P450 profiling tool that could be used for
early ADME estimation of new chemical entities.
[Back to top]
Rational
Design Approaches to Chemical Libraries for Hit Identification
Konstantin V. Balakin, Alexander V. Kozintsev, Alex S.
Kiselyov and Nikolay P. Savchuk
Sequencing of the human genome along with developments in
combinatorial synthesis and high-throughput biological screening
provide unparallel opportunities to drug discovery. It has
been noted that the increased number of synthesized and annotated
compounds did not yield the expected increase in number of
viable drug candidates. To address this problem, several novel
computation technologies have emerged for making combinatorial
library design cost-effective. Of particular interest for
the modern drug discovery are the structure-based or target-based
methods that use structural information about target proteins
and their small molecule ligands. In this work, we provide
an overview of selected advances in computational algorithms
for the rational selection of molecule libraries for the synthesis,
with emphasis on structure-based approaches. These include
a fusion of scaffold-linking method and combinatorial library
design, pharmacophore matching and informative library design,
and search by 3-D tree topological descriptors.
[Back to top]
Anti-Inflammatory
and Anti-Oxidant Activity of a New Class of Phenyl-Pyrazolone
Derivatives
C. Cusan, G. Altinier, S. Sosa, F. Sibilla, F. Bucar,
A. Tubaro, M. Prato, G. Spalluto and T. Da Ros
The anti-inflammatory activity of a new class of phenyl-pyrazolone
derivatives, structurally related to phenidone, has been evaluated
using the Croton oil ear test in mice as model of acute inflammation.
Derivative 5h reduces the percentage of oedema
similarly to indomethacin and more efficiently than phenylbutazone.
The anti-inflammatory activity of these two reference drugs
depends on their COX inhibition, but for the synthesized derivatives
it has not been demonstrated a significant COX or LOX inhibition,
as previously reported. While the anti-inflammatory activity
of phenidone is correlated to its anti-oxidant properties,
the redox potential of these compounds appears not decisive
in the inflammatory process inhibition. In order to investigate
the mechanism of action for these compounds, we quantified
their anti-oxidant activity and the lipophilicity, and a relationship
between the calculated logP and the percentage of
oedema reduction was found. We hypothesize that the anti-inflammatory
activity, recorded in vivo, could be related to lipophilic
parameter of these compounds.
[Back to top]
Fine-Grained Statistical Torsion
Angle Potentials are Effective in Discriminating Native Protein
Structures
Alessandro Albiero and Silvio C.E. Tosatto
Modelling of drug targets requires the reliable
selection of an accurate and representative structure from
large ensembles of alternate models. Statistical potentials
developed to discriminate native protein structures generally
represent pairwise interactions between atoms, which are less
sensitive to local conformational details. The discrimination
of local distortions is therefore particularly difficult.
Local interaction preferences, expressed through torsion angles,
are rarely used, as some controversy exists in the literature
regarding their discrimination power. The present study aims
to benchmark the efficiency of different implementations of
torsion angle propensities for selecting the native structure
from ensembles of well-constructed decoys. Several statistical
potentials derived from fine-grained discretisations of torsion
angle space are constructed and evaluated. Results from a
comparison with nine widely used statistical scoring functions
show the torsion angle potentials to be more effective in
recognising native structures and to improve with the number
of torsion angles considered. These data suggest local structural
propensities to be important for estimating the overall quality
of native-like models.
[Back to top]
Advanced Glycation End Products (AGEs) and their Receptor
(RAGE) System in Diabetic Retinopathy
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori
Matsui
Vascular complications are a leading
cause of blindness, end-stage renal failure, a variety of
neuropathies and accelerated atherosclerosis, which could
account for disabilities and high mortality rates in patients
with diabetes. There is a growing body of evidence that formation
and accumulation of advanced glycation end products (AGEs)
progress during normal aging, and at an extremely accelerated
rate in diabetes, thus being involved in the pathogenesis
of diabetic vascular complications. Furthermore, the interaction
by AGEs of their receptor, RAGE, activates down-stream signaling
and evokes inflammatory responses in vascular wall cells.
Therefore, inhibition of AGE formation or blockade of the
RAGE signaling may be a promising target for therapeutic intervention
to prevent diabetic vascular complications. This review discusses
the molecular mechanisms of diabetic retinopathy, especially
focusing on the AGE-RAGE system. Several types of inhibitors
of the AGE-RAGE system and their therapeutic implications
are also reviewed here.
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