Estudos computacionais para a seleção de inibidores naturais da proteína p53 mutada visando o combate ao adenocarcinoma colorretal

Abstract

Background: Colorectal cancer new cases affects about 1.8 million worldwide and the conventional treatments are often resistant. There are several factors related to treatment failures, including the mutation of p53 enzyme, that is involved in 50% of cases, causing the loss of its functionality as a tumor suppressor. Objectives: this work aimed to search new inhibitors for the mutant p53. Methods: The molecular modeling methodology were employed: i) the virtual screening in Sistemat-X database, ii) the molecular docking to calculate the interaction energy between the compounds found and the enzyme. Results: The virtual screening using 6,7-dihydro[1,4]dioxino[2,3-f][1,3]benzothiazol-2-amine fragments as a template, resulted in 216 analogous compounds that were submitted to Lipink's rule, and 127 compounds were approved. These compounds were docked with the mutant p53 using the iGEMDOCK program and the 20 best results, with the best binding energies, were submitted to molecular dynamics. The results indicated that the molecules have a good binding capacity, the molecules 1 and 128 showed the greater stability in hydrogen bonds, hydrophobic and van der Waals interactions. The flavonoids-derived compounds position interacts similarly to the thiazole ring of 6,7-dihydro[1,4]dioxino[2,3-f][1,3]benzothiazol-2-amine. Conclusion: The docking energies and the dynamics studies indicated that the compounds found through the virtual search can bind to the active site of the mutant p53, as well as to other enzymes involved in carcinogenic processes, consequently, being potential CCR inhibitors.