Combinatorial Chemistry & High Throughput Screening - Volume 8, Issue 5, 2005

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, solutionphase 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.

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.

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.

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.

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 selforganizing 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.

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.

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 0.204μM 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.

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.

A DNA sequence is a finite sequence of letters in the 4-letter DNA alphabet σ = {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 βglobins of eleven species.

In the article published Combinatorial Chemistry & High Throughput Screening (181-195, Vol. 8 No.2, Table 1) it was incorrectly stated by mistake of the author that PTK787/ZK 222584 is being developed by Novartis/Schering -Plough AG. PTK787/ZK 222584 is in fact being codeveloped by Schering AG, Berlin, Germany and Novartis, Basel, Switzerland.