Molecular docking of Indolin-2-one compounds as promising dual aurora B/FLT3 inhibitors as anticancer agents

Abstract

Aurora kinase enzymes perform important roles in mammals, mainly in cell cycle. Overexpression of these enzymes is related to tumor development and indicative of worsening of clinical conditions of diagnosed patients with cancer. Aurora kinases are promising targets in the search for new anticancer drugs, highlighting Aurora B. Other enzyme related to tumoral processes is the tyrosine kinase FLT3 and closely related to the acute myeloid leukemia (AML). FLT3 enzyme is expressed in membranes of precursor hematopoietic cells and have important role in cellular differentiation, proliferation and multiplication. In AML disease, normally, occurs hyperstimulation or mutations of FLT3 enzyme, leading to exacerbated cellular proliferation and lower response to standard cytotoxic agents. FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in searching for promising new anticancer compounds, mainly to AML. This work was designed to study and understand the interactions between two different targets, Aurora B and FLT3 enzymes, and several indolin-2-one derivatives, structurally similar to sunitinib drug. Molegro Virtual Docker software was utilized in docking estimates and the human Aurora B and FLT3 structures obtained from PDB (4AF3 and 4XUF) with hesperadin and quizartinib used as reference compounds, respectively. The mathematical models, performed in Chemoface program, achieved R 2 of 0.94 and 0.82, suggesting that the binding conformations of the ligands with human Aurora B and FLT3 are reasonable and the data can be used to predict the level of interaction of other Aurora B and FLT3 indolin-2-one inhibitors with similar molecular patterns. Compound 1 showed more stable interaction energies, -225.90 kcal.mol -1 to Aurora B and -233.25 kcal.mol -1 to FLT3, among all studied inhibitors with experimental data available, while sunitinib was the least stable (-135.63 kcal.mol -1 ) considering the Aurora B enzyme and one of the least stable (-160.94 kcal.mol -1 ) to FLT3. Four new proposed indolin-2-one derivatives (IAF61, IAF63, IAF66 and IAF79) were highlighted as promising compounds for future synthesis and biological evaluation against human Aurora B, other six (IAF70, IAF72, IAF75, IAF80, IAF84 and IAF88) against FLT3 and one compound (IAF79) as a promising compound with dual Aurora B/FLT3 activity. Besides that, the molecular pattern evidenced in our studies must be exploited synthetically in searching for new compounds that may become a drug used in cancer treatment, including AML, thus validating and ratifying our docking studies.