Análise in silico da farmacocinética e farmacodinâmica do composto benzotiazólico com potencial antitumoral contra linhagem de adenocarcinoma gástrico

Abstract

Gastric adenocarcinoma has high incidence and mortality rates worldwide. The aim of this study was to evaluate the antitumor activity of benzothiazole AFN01 against ACP03 gastric adenocarcinoma cell line. Furthermore, computational prediction of the pharmacokinetics and pharmacodynamics of this molecule and the molecular docking with the relevant pharmacological target found were performed. The MTT assay was performed to evaluate the cytotoxic potential of the compound and fluorescence microscopy was used to measure cell death induction with Fluorescein Diacetate, Hoechst 33342 and Propidium Iodide fluorophores. The result of the concentration-response curve obtained by MTT assay revealed a relevant cytotoxic effect against the lineage with IC50 values around 17.24 μM at 24 h, 8.23 μM at 48 h and 1.39 μM at 72 h of exposure. AFN01 was able to induce apoptosis at 1 and 2 μM. Computational analyses identified relevant pharmacokinetic properties such as positive intestinal absorption, inhibition of CYP1A2, CYP2C9 and CYP3A4, as well as weak inhibition of hERG and class III acute oral toxicity. The pharmacodynamic prediction identified molecular targets related to antitumor activity. The enzyme TDP1 was selected for molecular docking, indicating that benzothiazole has a binding energy of -7.5 kcal/mol and important interactions with catalytic site residues of the enzyme. In conclusion, the AFN01 benzothiazole compound is an excellent candidate for the treatment of gastric adenocarcinoma, with good predicted pharmacokinetic parameters and a potentially new molecular target.