Computational Studies in Drug Design Against Cancer.

BACKGROUND: The application of in silico tools in the development of anti cancer drugs. OBJECTIVE: The summing of different computer aided drug design approaches that have been applied in the development of anti cancer drugs. METHODS: Structure based, ligand based, hybrid protein-ligand pharmacophore methods, Homology modeling, molecular docking aids in different steps of drug discovery pipeline with considerable saving in time and expenditure. In silico tools also find applications in the domain of cancer drug development. RESULTS: Structure-based pharmacophore modeling aided in the identification of PUMA inhibitors, structure based approach with high throughput screening for the development of Bcl-2 inhibitors, to derive the most relevant protein-protein interactions, anti mitotic agents; I-Kappa-B Kinase ß (IKK- ß) inhibitor, screening of new class of aromatase inhibitors that can be important targets in cancer therapy. CONCLUSION: Application of computational methods in the design of anti cancer drugs was found to be effective.

In silico and In vivo Toxicological Evaluation of Cissampelos Sympodialis Secondary Metabolites in Rattus Norvegicus.

Cissampelos sympodialis is a plant in northeastern Brazil used by the populace for treating respiratory diseases. Several studies have shown that ethanol leaf extracts have immunomodulatory and anti-inflammatory activities. Infusions are widely used, popular, and an ancient technique in traditional medicine, using hot water alone as the means of extraction. This study aimed to investigate acute toxicological potential of leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg to Rattus norvegicus, combined with an in silico study of 117 alkaloids present in the Cissampelos genus; five (5) of which were determined to have high toxicity (21, 8, 93, 32 and 88), and five (5) having both low toxicity (57, 77, 28, 25 and 67) and low liver metabolism. The in vivo toxicological evaluation showed that male water consumption decreased, and the feed intake decreased in both sexes. Yet, the figures as to change in weight gain of the animals were not statistically sufficient. As for the biochemical parameters, there was an increase in urea, and decreases in uric acid and AST in males. In females, there was a decrease in albumin and globulin which consequently leads to a total protein decrease. Despite biochemical changes suggestive of kidney damage, the histological sections revealed no kidney or liver changes. The results therefore indicate that despite presenting alkaloids which may be toxic, the genus Cissampelos, or leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg present low toxicity.

Enzymatic Targets in Trypanosoma brucei.

One of the most neglected disease is the Sleeping sickness or Human African Trypanosomiasis (HAT), which is mostly restricted to poor regions of Africa. The disease is caused by parasitic infection with Trypanosoma brucei (T. brucei), and is acquired through the bite of the tsetse fly. In the first stage of the disease, the parasite is in the blood, but in stage 2, the infective form reaches the brain, causing great weakness and death. The few existing drugs against this infection, are highly toxic, and can cause the emergence of resistant forms of the parasite. Also, these drugs are not readily available. New drugs are needed. Many researchers are investigating new enzyme targets for the parasite, searching for more efficient and selective inhibitors that are capable to cause the parasite death with less toxicity to the host. Trypanothione reductase, farnesyl diphosphate synthase, 6-phospho-gluconate dehydrogenase, and UDP 4'-galactose epimerase are some of the enzymes involved in the studies reported on this review. In addition, we have applied ligandbased- virtual screening, using Random Forest associated with structure-based-virtual screening (docking), to a small dataset of 225 alkaloids from the Menispermaceae family (in-house data bank). The aim of this study is to select structures with potential inhibitory activity against trypanothione reductase from Trypanosoma brucei. The computer-aided drug design study selected certain alkaloids that might be worth further investigation.

Chemometric studies on potential larvicidal compounds against Aedes aegypti.

The mosquito Aedes aegypti (Diptera, Culicidae) is the vector of yellow and dengue fever. In this study, chemometric tools, such as, Principal Component Analysis (PCA), Consensus PCA (CPCA), and Partial Least Squares Regression (PLS), were applied to a set of fifty five active compounds against Ae. aegypti larvae, which includes terpenes, cyclic alcohols, phenolic compounds, and their synthetic derivatives. The calculations were performed using the VolSurf+ program. CPCA analysis suggests that the higher weight blocks of descriptors were SIZE/SHAPE, DRY, and H2O. The PCA was generated with 48 descriptors selected from the previous blocks. The scores plot showed good separation between more and less potent compounds. The first two PCs accounted for over 60% of the data variance. The best model obtained in PLS, after validation leave-one-out, exhibited q(2) = 0.679 and r(2) = 0.714. External prediction model was R(2) = 0.623. The independent variables having a hydrophobic profile were strongly correlated to the biological data. The interaction maps generated with the GRID force field showed that the most active compounds exhibit more interaction with the DRY probe.

Synthesis, structure-activity relationships (SAR) and in silico studies of coumarin derivatives with antifungal activity.

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO(2) and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2(cv) of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

Preliminary antifungal and cytotoxic evaluation of synthetic cycloalkyl[b]thiophene derivatives with PLS-DA analysis.

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcus neoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). For antiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and for antiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]- 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA) applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.