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Indolin-2-one Derivatives: Theoretical Studies Aimed at Finding More Potent Aurora B Kinase Inhibitors

[ Vol. 16 , Issue. 2 ]

Author(s):

Ítalo Antônio Fernandes, Tamiris Maria de Assis, Isael Aparecido Rosa and Elaine Fontes Ferreira da Cunha*   Pages 138 - 152 ( 15 )

Abstract:


Background: Aurora kinases perform important roles in mammals, mainly in cell cycle. Overexpression of these enzymes is related to tumor development and is indicative of worsening of clinical conditions. Aurora kinases are promising targets in the search for new anticancer drugs, in particular, Aurora B.

Methods: This work was designed to study and understand the interactions between human Aurora B and several indolin-2-one derivatives, structurally similar to sunitinib. MVD software was utilized in docking analyses of indolin-2-one derivatives. Human Aurora B kinase was obtained from the PDB (4AF3) and redocked with hesperadin, which was used as a reference compound. The predicted model of the training group, considering 21 amino acid residues, performed in Chemoface, achieved an R2 of 0.945, suggesting that the binding conformations of the ligands with human Aurora B are reasonable and the data can be used to predict the interaction energy of other Aurora B inhibitors indolin-2-one derivatives.

Results: MolDock Score energy for compound 1 showed more stable interaction energy (-225.90 kcal.mol-1) then the other inhibitors studied, while sunitinib was the least stable (-135.63 kcal.mol-1). Compounds 1-45, hesperadin and sunitinib, interacted with Glu171 (–NH from indolinonic moiety), and the majority of them with Ala173 (C=O from indolinonic moiety) via hydrogen bonds, thus these two residues are relevant for potency.

Conclusion: Docking studies and biological activity in literature show subunits likely for structural optimizations, leading to four new proposed derivatives (IAF61, IAF63, IAF66, IAF79) as promising compounds for synthesis and biological evaluation against human Aurora B, validating and ratifying the docking studies.

Keywords:

Aurora B kinase, aurora B kinase inhibitors, indolin-2-one derivatives, cancer, medicinal chemistry, anticancer compounds, computational chemistry, docking.

Affiliation:

Laboratorio de Modelagem Molecular, LABGQC, Chemistry Department, Federal University of Lavras, Lavras, MG, Laboratorio de Modelagem Molecular, LABGQC, Chemistry Department, Federal University of Lavras, Lavras, MG, Laboratorio de Modelagem Molecular, LABGQC, Chemistry Department, Federal University of Lavras, Lavras, MG, Laboratorio de Modelagem Molecular, LABGQC, Chemistry Department, Federal University of Lavras, Lavras, MG

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