The zebrafish Danio rerio appears to be as an alternative experimental model mainly used on toxicological evaluations since the 1990s. In this chapter, we illustrate using a histopathological study the evaluation of a complex phytopreparation with janaguba milk (TPJM, used in popular medicine), which was administrated in zebrafish by immersion in water. We determined (1) lethal concentration 50 (LC50) – 1188.54 μg/mL; (2) the behavioral changes; and (3) the acute administration of TPJM modifications (48 h) at concentrations 500, 750, 1000, and 1500 μg/mL, on the histopathological parameters of the gills, kidneys, and liver. Also the concentrations of 1000 and 1500 μg/mL caused significant damage to the gill tissue and produced a high rate of histological changes in the liver. The kidneys showed greater changes at concentrations of 750, 1000, and 1500 μg/mL. Based on the percentage of TPJM extracts that was only 1.85%, the LC50 was calculated as 475 mg/kg; according to traditional indication, only 6 tablespoons/day is consumed; and it is possible to infer that only 0.5 g of active ingredient is ingested by an adult user per day, corresponding to a dose of 7.14 mg/kg, which is far from the toxic effects, demonstrating low toxicity of TPJM.

Mycobacterium abscessus subsp. massiliense (Mabs) causes chronic infections, which has led to the need for new antimycobacterial agents. In this study, we investigated the antimycobacterial and anti-inflammatory activities of the ethyl acetate fraction of Bixa orellana leaves (BoEA) and ellagic acid (ElAc). In silico analysis predicted that ElAc had low toxicity, was not mutagenic or carcinogenic, and had antimicrobial and anti-inflammatory activities. Apparently, ElAc can interact with COX2 and Dihydrofolate reductase (DHFR) enzymes, which could explain both activities. In vitro analysis showed that BoEA and ElAc exerted antimicrobial activity against Mabs (minimum inhibitory concentration of 1.56, 1.56 mg/mL and bactericidal concentration of 6.25, 3.12 mg/mL, respectively. Clarithromycin showed MIC and MBC of 1 and 6 µg/mL). Treatment with BoEA or ElAc increased survival of Tenebrio molitor larvae after lethal infection with Mabs and reduced carrageenan-induced paw edema in mice, around 40% of edema volume after the fourth hour, similarly to diclofenac. In conclusion, BoEA and ElAc exert antimicrobial effects against Mabs and have anti-inflammatory effects, making them potential sources of antimycobacterial drugs. The biological activities of ElAc may be due to its high binding affinities predicted for COX2 and DHFR enzymes.

Background: Prostate cancer is the most common cancer in men, especially after the age of 50. It is a malignant disease that is increasing due to the increased life expectancy of the world population. Its development and progression are dependent on androgenic stimulation. Objectives: This study aimed to identify potential inhibitors with anti-prostate cancer activity through the application of chemoinformatics tools, exploring the Princeton (~1.2 million compounds) and Zinc Drug (~175 million compounds) databases. Methods: The methodology used several computational techniques, such as ROCS (Rapid Chemical Structure Superposition) and EON (Electrostatic Potential Screening), predictions of pharmacokinetic and toxicological properties, molecular docking, synthetic accessibility, biological activity, and molecular dynamics. Results: At the end of all these virtual screening steps, the study resulted in four promising potential candidates for the treatment of prostate cancer: the molecules ZINC34176694, ZINC03876158, ZINC04097308, and ZINC03977981, which exhibited all the desirable pharmacokinetic parameters (ADME/Tox) for a potential drug. Conclusions: Docking and molecular dynamics studies demonstrate stability and interaction with the androgen receptor of the selected compounds, showing them to be promising candidates for the development of new drugs.

Background: This study began with a search in three databases, totaling six libraries (ChemBridge-DIVERSet, ChemBridge-DIVERSet-EXP, Zinc_Drug Database, Zinc_Natural_Stock, Zinc_FDA_BindingDB, Maybridge) with approximately 2.5 million compounds with the aim of selecting potential inhibitors with antiproliferative activity on the chimeric tyrosine kinase encoded by the BCR-ABL gene. Methods: Through hierarchical biochemoinformatics, ADME/Tox analyses, biological activity prediction, molecular docking simulations, synthetic accessibility and theoretical synthetic routes of promising compounds and their lipophilicity and water solubility were realized. Results: Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the top100/base (600 structures), in comparison with the commercial drug imatinib, showed that only nine exhibited the desired properties. In the prediction of biological activity, the results of the nine selected structures ranged from 13.7% < Pa < 65.8%, showing them to be potential protein kinase inhibitors. In the molecular docking simulations, the promising molecules LMQC01 and LMQC04 showed significant values in molecular targeting (PDB 1IEP—resolution 2.10 Å). LMQC04 presented better binding affinity (∆G = −12.2 kcal mol⁻¹ with a variation of ±3.6 kcal mol⁻¹) in relation to LMQC01. The LMQC01 and LMQC04 molecules were advanced for molecular dynamics (MD) simulation followed by Molecular Mechanics with generalized Born and Surface Area solvation (MM-GBSA); the comparable, low and stable RMSD and ΔE values for the protein and ligand in each complex suggest that the selected compounds form a stable complex with the Abl kinase domain. This stability is a positive indicator that LMQC01 and LMQC04 can potentially inhibit enzyme function. Synthetic accessibility (SA) analysis performed on the AMBIT and SwissADME webservers showed that LMQC01 and LMQC04 can be considered easy to synthesize. Our in silico results show that these molecules could be potent protein kinase inhibitors with potential antiproliferative activity on tyrosine kinase encoded by the BCR-ABL gene. Conclusions: In conclusion, the results suggest that these ligands, particularly LMQC04, may bind strongly to the studied target and may have appropriate ADME/Tox properties in experimental studies. Considering future in vitro or in vivo assays, we elaborated the theoretical synthetic routes of the promising compounds identified in the present study. Based on our in silico findings, the selected ligands show promise for future studies in developing chronic myeloid leukemia treatments.