Combinatorial Chemistry & High Throughput
Screening, Vol. 8, No. 5, 2005
Contents
Combinatorial Synthesis and
Computer-Aided Design of Anti-HIV Drugs
Guest Editor: S.P. Gupta
Editorial
Pp.375-375
S. P. Gupta
[Abstract] Combinatorial
Synthesis of Anti-HIV Agents-A Review
Pp.377-385 Dharmarajan
Sriram, Perumal Yogeeswari and Ananantha Naik Nagappa Combinatorial
Chemistry as a Tool for Targeting Different Stages of the Replicative HIV-1
Cycle Pp.387-401 Claudia
Mugnaini, Elena Petricci, Federico Corelli and Maurizio Botta “In
Silico” Design of Potential Anti-HIV Actives Using Fragment Descriptors Pp.403-416 A.
Varnek and V.P. Solov’ev Virtual
Screening for Anti-HIV-1 RT and Anti-HIV-1 PR Inhibitors from the Thai
Medicinal Plants Database: A Combined Docking with Neural Networks Approach Pp.417-429 Chak
Sangma, Daungmanee Chuakheaw, Nipa Jongkon, Kittipong Saenbandit, Peerapol
Nunrium, Putchong Uthayopas and Supa Hannongbua Topological
Descriptors in Modeling the HIV Inhibitory Activity of 2-Aryl-3-
pyridyl-thiazolidin-4-ones
Pp.431-437 Y.S.
Prabhakar, R.K. Rawal, M.K. Gupta, V. Raja Solomon and S.B. Katti Synthesis
and QSAR Studies on Thiazolidinones as Anti-HIV Agents Pp.439-443 Ravindra
K. Rawal, V. Raja Solomon, Yenamandra S. Prabhakar, S.B. Katti and E. De Clercq General
Articles Cleavage
of Oximes Using a Solid Supported Hypervalent Organoiodine Reagent Pp.445-447 Atul
Kumar, Pervez Ahmad, Akanksha and Ram Awatar Murya The
Sieve Ratio for Characterization and Similarity Analysis of DNA Sequences Pp.449-453 Ping-an
He Abstracts [Back to top] S.
P. Gupta In the present era, acquired
immunodeficiency syndrome (AIDS) is the most fatal disorder for which no
completely successful chemotherapy could be developed so far. The causative
agent of AIDS has been identified as a retrovirus of type-1 (HIV-1). Therefore,
a great attention has been focused in the recent years on the design and
development of anti-HIV drugs. The last five years has seen an explosion in the
exploration and adoption of combinatorial synthesis of drugs with the
continuous development of high throughput screening. Compound libraries
designed to produce specific inhibitors of therapeutic target proteins have
generated significant interest in drug discovery research, resulting into the
discovery of many lead compounds. The present issue is therefore devoted to
publish some timely reviews on the combinatorial synthesis of anti-HIV drugs
and their computer-aided design. So far various methods have been
developed in combinatorial chemistry, which include solid-phase synthesis,
solution-phase synthesis, fluorous-phase synthesis, and combination of all
them. Of these, the solid-phase synthesis (SPS) has been found to play a
decisive role in the ongoing development of combinatorial chemistry. Therefore,
in article 1, Sriram et al. have presented a survey of solid-phase
synthesis of some anti-HIV drugs that include HIV-1 reverse transcriptase
inhibitors, protease inhibitors, HIV-1 function inhibitors such as adsorption
inhibitors, CCR5 antagonists, and HIV-1 Tat-TAR inhibitors. A similar article
(article 2) describing in more detail the combinatorial synthesis has been
presented by Mugnaini et al. Computer-aided design of anti-HIV
compounds based on generation of virtual combinatorial libraries followed by
their screening, using QSAR models, represents a promising technique to produce
novel actives. In article 3, Varnek and Solov’ev describe the design of several
new compounds possessing high anti-HIV activities, using substructural
molecular fragments method (SMF) of computer-aided techniques of drug design.
The virtual screening approach for docking small molecules into a known protein
structure is a powerful tool for drug design. Sangma et al. describe in article
4 a combined docking and network approach to screen anti-HIV drugs from active
compounds available in the Thai medicinal plants database. Article 5 by
Prabhakar et al. presents an analysis of the dependence of the HIV-1 RT
inhibitory activity of 2-(2,6-dihalophenyl)-3-(substituted
pyridin-2-yl)-thiazolidin-4-ones on some topological descriptors obtained from
DRAGON software, in which simple topological descriptors (TOPO), Galvez
topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO)
have been found to yield good predictive models for the activity of these
compounds. Finally, article 6 by Rawal et al. describes some studies on
the synthesis of a series of some 4-thiazolidinones and the screening of their
anti-HIV activity, along with a QSAR study on them. I thank all the authors of this
issue for their excellent stimulating contributions and hope that readers will
greatly enjoy reading these articles as I did and that these contributions will
be of great value to those involved in the study of design and development of
anti-HIV drugs. [Back to top] Dharmarajan
Sriram, Perumal Yogeeswari and Ananantha Naik Nagappa Combinatorial chemistry has been
well recognized as an important tool of drug discovery. An ongoing hand is to
integrate the combinatorial approach with fundamentals of medicinal chemistry
and rational drug design. The last five years has seen an explosion in the
exploration and adoption of combinatorial techniques. Indeed, it is difficult
to identify any other topic in chemistry that has ever caught the imagination
of chemists with such fervor and with the continuous development of high
throughput screening methods. There is a growing need for the synthesis of a
large number of molecules. Compound libraries designed to produce specific
inhibitors of therapeutic target proteins have generated significant interest
in drug discovery research. Combinatorial chemistry provides the opportunity to
generate large libraries of compounds for biological testing. A literature
search revealed that many lead compounds have indeed been discovered from
libraries and this review presents a survey of combinatorial synthesis of HIV-1
reverse transcriptase inhibitors, protease inhibitors, HIV-1 function
inhibitors such as adsorption inhibitors, CCR5 antagonists and HIV-1 Tat-tar
inhibitors that can be developed as potential anti-HIV drugs. [Back to top] Claudia
Mugnaini, Elena Petricci, Federico Corelli and Maurizio Botta In the present era, acquired
immunodeficiency syndrome (AIDS) is the most fatal disorder for which no
completely successful chemotherapy has been developed so far. The pandemic
spread of this disease has prompted an unprecedented scientific and clinical
effort to understand and combat it. A number of targets has been identified to
stop the replication of the virus at different stages of its life cycle:
Reverse Transcriptase (RT), protease (PR) and CCR5 are the most promising
targets. Although highly active antiretroviral therapy (HAART) has been
effective in reducing the mortality and morbidity in recent years, adverse side
effects of the chemotherapy, patient non-compliance and the development of
viral resistance remain major problems. With the aim to find better drug
candidates with minor adverse side effects in recent years, several groups have
investigated combinatorial approaches for the generation of libraries of HIV PR
inhibitors while only few contributions to the preparation of libraries of HIV
Reverse Transcriptase (RT) and CCR5 inhibitors are available. This review
summarizes the recent developments of combinatorial chemistry in this area. [Back to top] A.
Varnek and V.P. Solov’ev Substructural Molecular Fragments
(SMF) method was applied for computer-aided design of new compounds potentially
possessing high anti-HIV activities: tetrahydroimidazobenzodiazepinone (TIBO)
derivatives and 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)
derivatives. Using available experimental data, the SMF method was first
applied to build QSAR models based on fragment descriptors (atom/bond sequences
and “augmented atoms”). The focused virtual combinatorial libraries containing
891 TIBO derivatives and 2640 HEPT derivatives were then generated
systematically attaching selected substituents to corresponding Markush
structures. Finally, a screening of those libraries using developed QSAR models
led to several hits potentially possessing high anti-HIV activity. [Back to top] Chak
Sangma, Daungmanee Chuakheaw, Nipa Jongkon, Kittipong Saenbandit, Peerapol
Nunrium, Putchong Uthayopas and Supa Hannongbua The virtual screening approach
for docking small molecules into a known protein structure is a powerful tool
for drug design. In this work, a combined docking and neural network approach,
using a self-organizing map, has been developed and applied to screen
anti-HIV-1 inhibitors for two targets, HIV-1 RT and HIV-1 PR, from active
compounds available in the Thai Medicinal Plants Database. Based on nevirapine
and calanolide A as reference structures in the HIV-1 RT binding site and
XK-263 in the HIV-1 PR binding site, 2,684 compounds in the database were
docked into the target enzymes. Self-organizing maps were then generated with
respect to three types of pharmacophoric groups. The map of the reference
structures were then superimposed on the feature maps of all screened
compounds. Only the structures having similar features to the reference
compounds were accepted. By using the SOMs, the number of candidates for HIV-1
RT was reduced to six and nine compounds consistent with nevirapine and
calanolide A, respectively, as references. For the HIV-1 PR target, there are
135 screened compounds showed good agreement with the XK-263 feature map. These
screened compounds will be further tested for their HIV-1 inhibitory
affinities. The obtained results indicate that this combined method is clearly
helpful to perform the successive screening and to reduce the analyzing step
from AutoDock and scoring procedure. [Back to top] Y.S.
Prabhakar, R.K. Rawal, M.K. Gupta, V. Raja Solomon and S.B. Katti The HIV-1 RT inhibitory activity
of 2-(2,6-dihalophenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones has
been analyzed with different topological descriptors obtained from DRAGON
software. Here, simple topological descriptors (TOPO), Galvez
topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO)
have been found to yield good predictive models for the activity of these
compounds. The correlations obtained from the TOPO class descriptors
suggest that less extended or compact saturated structural templates would be
better for the activity. The participating GVZ class descriptors suggest
that they have same degree of influence on the activity. In 2DAUTO
class, the large participation of descriptors of lags seven and three indicate
the association of activity information with the seven and three centered
structural fragments of these compounds. The physicochemical weighting
components of these descriptors suggest homogeneous influence of mass, volume,
electronegativity and/ or polarizability on the activity. [Back to top] Ravindra
K. Rawal, V. Raja Solomon, Yenamandra S. Prabhakar, S.B. Katti and E. De Clercq selected 4-thiazolidinone have
been synthesized and tested as anti-HIV activity. The results of the in
vitro tests showed that one of the compounds, 5, inhibited the enzyme at
0.204mM concentration with minimal toxicity
to MT-4 cell. Furthermore, the QSAR studies indicated the role of PMIZ, Ovality
and Total energy content of the compounds in rationalizing the activity. [Back to top] Atul
Kumar, Pervez Ahmad, Akanksha and Ram Awatar Murya A facile and efficient oxidative
cleavage of oximes to form carbonyl compounds is reported using phenyl iodonium
(III) diacetate (PIDA) and polymer supported polydiacetoxyiodostyrene.
Regeneration of carbonyl compounds from corresponding oximes is an important
reaction, since oxime derivatives constitute one of the primary methods for
purification and characterization of carbonyl compounds. This process overcomes
many of the disadvantages associated with other oxidative methods such as long
reaction times, difficulties in isolation of products and formation of over
oxidized products. [Back to top] Ping-an
He A DNA sequence is a finite
sequence of letters in the 4-letter DNA alphabet ∑ = {A, C, G, T}.
A set of condensed matrices was constructed to represent DNA sequences based on
the sieve ratios of trinucleotide in sequence. Then, leading eigenvalues of
these matrices were computed and considered as invariants for the DNA
sequences. Similarity and dissimilarity analysis based on condensed matrices
are given for eleven exon-1 genes of b-globins
of eleven species.
Editorial