QSAR Modeling for Multi-Target Drug Discovery: Designing Simultaneous Inhibitors of Proteins in Diverse Pathogenic Parasites.

Parasitic diseases remain as unresolved health issues worldwide. While for some parasites the treatments involve drug combinations with serious side effects, for others, chemical therapies are inefficient due to the emergence of drug resistance. This urges the search for novel antiparasitic agents able to act through multiple mechanisms of action. Here, we report the first multi-target model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mt-QSAR-MLP) to virtually design and predict versatile inhibitors of proteins involved in the survival and/or infectivity of different pathogenic parasites. The mt-QSAR-MLP model exhibited high accuracy (>80%) in both training and test sets for the classification/prediction of protein inhibitors. Several fragments were directly extracted from the physicochemical and structural interpretations of the molecular descriptors in the mt-QSAR-MLP model. Such interpretations enabled the generation of four molecules that were predicted as multi-target inhibitors against at least three of the five parasitic proteins reported here with two of the molecules being predicted to inhibit all the proteins. Docking calculations converged with the mt-QSAR-MLP model regarding the multi-target profile of the designed molecules. The designed molecules exhibited drug-like properties, complying with Lipinski's rule of five, as well as Ghose's filter and Veber's guidelines.

Thiophene-thiosemicarbazone derivative (L10) exerts antifungal activity mediated by oxidative stress and apoptosis in C. albicans.

Reactive oxygen species (ROS) cause cell damage and death. To reverse these effects, cells produce substances such as reduced glutathione (GSH) that serve as substrates for antioxidant enzymes. One way to combat microbial resistance includes nullifying the effect of glutathione in microbial cells, causing them to die from oxidative stress. The compound 2-((5-nitrothiophen-2-yl)methylene)-N-(pyridin-3-yl) hydrazine carbothioamide (L10) is a new thiophene-thiosemicarbazone derivative with promising antifungal activity. The aim of this study was to evaluate its mechanism of action against Candida albicans using assays that evaluate its effects on redox balance. Treatment with L10 promoted significant changes in the minimum inhibitory concentration (MIC) values in ascorbic acid and GSH protection tests, the latter increasing up to 64-fold of the MIC. Using nuclear magnetic resonance, we demonstrated interaction of L10 and GSH. At concentrations of 4.0 and 8.0 µg/mL, significant changes were observed in ROS production and mitochondrial membrane potential. The cell death profile showed characteristics of initial apoptosis at inhibitory concentrations (4.0 µg/mL). Transmission electron microscopy data corroborated these results and indicated signs of apoptosis, damage to plasma and nuclear membranes, and to mitochondria. Taken together, these results suggest a possible mechanism of action for L10 antifungal activity, involving changes in cellular redox balance, ROS production, and apoptosis-compatible cellular changes.

Recent Theoretical Studies Concerning Important Tropical Infections.

Neglected Tropical Diseases (NTDs) form a group of diseases that are strongly associated with poverty, flourish in impoverished environments, and thrive best in tropical areas, where they tend to present overlap. They comprise several diseases, and the symptoms vary dramatically from disease to disease, often causing from extreme pain, and untold misery that anchors populations to poverty, permanent disability, and death. They affect more than 1 billion people worldwide; mostly in poor populations living in tropical and subtropical climates. In this review, several complementary in silico approaches are presented; including identification of new therapeutic targets, novel mechanisms of activity, high-throughput screening of small-molecule libraries, as well as in silico quantitative structure-activity relationship and recent molecular docking studies. Current and active research against Sleeping Sickness, American trypanosomiasis, Leishmaniasis and Schistosomiasis infections will hopefully lead to safer, more effective, less costly and more widely available treatments against these parasitic forms of Neglected Tropical Diseases (NTDs) in the near future.

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 µM and 11.38 µM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 µM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 µM).

Molecular Docking Studies Applied to a Dataset of Cruzain Inhibitors.

BACKGROUND: Chagas' disease is one of the main causes of heart failure in developing countries. The disadvantages of current therapy include the undesirable side-effects, resistance, and therapeutic adhesion. The development of new efficient and safe drugs is, therefore, an issue of extreme importance. OBJECTIVES: In order to gain a better understanding of how the compounds interact with the target, computational methods are essential. METHODS: In this theoretical study, we report a docking protocol applied to a dataset of 173 cruzain inhibitors with IC50 values of less than 10 µM, belonging 16 different chemical classes. A preliminary analysis was performed, where the best protein structure for the study was identified. RESULTS: The enzyme was validated by redocking and a fingerprint graph for the ligand-enzyme interactions was generated, allowing the identification of the main amino acid residues related to the activity. Additionally, a larger cluster was generated, allowing the visualization of the orientation of the compounds and providing binding information for the different classes of compounds as well as their interaction in the cruzain active site. Amino acid residues other than those known as the catalytic triad (Gly23, Cys25, and Gly65) were identified, for example, Gln19 and Asp158. CONCLUSION: This provides a better insight into the mode of interaction of various cruzain inhibitors, which show IC50 values in the nanomolar range but which do not interact with the triad. These findings can help researchers to find new cruzain inhibitors for use in the fight against the Chagas disease.

Experimental methodologies and evaluations of computer-aided drug design methodologies applied to a series of 2-aminothiophene derivatives with antifungal activities.

Fifty 2-[(arylidene)amino]-4,5-cycloalkyl[b]thiophene-3-carbonitrile derivatives were screened for their in vitro antifungal activities against Candida krusei and Cryptococcus neoformans. Based on experimentally determined minimum inhibitory concentration (MIC) values, we conducted computer-aided drug design studies [molecular modelling, chemometric tools (CPCA, PCA, PLS) and QSAR-3D] that enable the prediction of three-dimensional structural characteristics that influence the antifungal activities of these derivatives. These predictions provide direction with regard to the syntheses of new derivatives with improved biological activities, which can be used as therapeutic alternatives for the treatment of fungal infections.

SAR, QSAR and docking of anticancer flavonoids and variants: a review.

Flavonoids are phenolic compounds, secondary metabolites of plants that cause several benefits to our health, including helping the treatment against cancer. These pharmacological properties are associated with the ability of flavonoids in attenuating the generation of reactive oxygen species, acting as chelate compounds or affecting the oxi-redox cycle. In spite of the large number of information in term of SAR and QSAR, no recent review has tabulated and discussed in detail these data. In view of this, we bring here a detailed discussion of the structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) models. We have also analyzed the correlation between the chemical structure of flavonoids and analogues to their anticancer activities. A large number of methodologies have been used to identify the characteristics of these compounds with their potential anticancer: multiple linear regression, principal components analysis, comparative molecular field analysis, comparative molecular similarity indices analysis, partial least squares, neural networks, configuration of classification and regression trees, Free-Wilson, docking; using topological, structural and enthalpies' descriptors. We also discussed the use of docking models, together with QSAR models, for the virtual screening of anticancer flavonoids. The importance of docking models to the medicinal chemistry of anticancer flavonoids has increased in the last decade, especially to help in identifying the structural determinants responsible for the activity. We tabulated here the most important examples of virtual screening determined for anticancer flavonoids and we highlighted the structural determinants. The mode of action, the most potent anticancer flavonoids and hints for the structural design of anticancer flavonoids are revised in details and provided here.