Análise computacional da propriedade anticâncer de derivados de juglona

Abstract

During 2008 and 2012, the overall incidence of cancer increased from 12.7 million to 14.1 million, following a prediction of a 70% increase in the incidence of cases by 2030. Chemotherapy has been facing difficulties such as resistance and low response to drugs routinely used in the clinic, leading to inefficient treatments or with many side effects. In this scenario, ADME-TOX properties, as well as pharmacodynamic targets, are important parameters for selection of drug candidates and can be predicted by computational techniques. Thus, the objective of this work was to evaluate the pharmacokinetic and pharmacodynamic profile of thioethers derived from juglonas. To this end, 16 compounds were selected and, with the help of the MarvinSketch program, the two-dimensional structure was designed to obtain the SMILES code. These codes were used for physico-chemical, pharmacokinetic and pharmacodynamic evaluation by the Molinspiration, admetSAR and SwissTarget Prediction servers. Based on the predicted targets, we selected crystallographic structures in the Protein Data Bank database for molecular docking with the AutoDock Vina and GOLD software. The drug-likness analysis revealed that all 16 thioether compounds did not violate any of the rules of Lipinski's 5. Generally, the molecules have good absorption, distribution in mitochondria, high promiscuity to the inhibition of CYP 450 proteins, low toxicity with respect to hERG gene inhibition. Among the main biological targets predicted, the enzymes TDP1 and TOP1 were highlighted by the fact that inhibition has applications in cancer therapy. The two programs revealed CNN03 as the best binder for TDP1 and TOP1, and it was possible to identify the interaction with active residues of the enzymes. Therefore, through bioinformatics methodologies, it was possible to obtain information on the pharmacokinetic and pharmacodynamic profile of 16 compounds and to investigate the main residues involved in the interaction with the selected molecules.