The glycogen synthase kinase 3β (GSK-3β) is a protein kinase involved in regulating numerous physiological processes such as embryonic development, transcription, insulin action, cell division cycle and multiple neuronal functions. The overexpression of this enzyme is related to many diseases such as schizophrenia, Alzheimer's disease, diabetes and cancer. One of the basic methods of treatment in these cases is the usage of ATP-competitive inhibitors. A significant group of such compounds are indirubin and its analogs, e.g., oxindole derivatives. The compounds considered in this work are 112 newly designed oxindole derivatives. In the first stage, such molecular properties of considered compounds as toxicity and LogP were estimated. The preliminary analysis of the binding capabilities of considered compounds towards the GSK-3β active site was conducted with the use of the docking procedure. Based on obtained molecular properties and docking simulations, a selected group of complexes that were analyzed in the molecular dynamics stage was nominated. The proposed procedure allowed for the identification of compounds such as Oxind_4_9 and Oxind_13_10, which create stable complexes with GSK-3β enzyme and are characterized by the highest values of binding affinity. The key interactions responsible for stabilization of considered ligand-protein complexes were identified, and their dynamic stability was also determined. Comparative analysis including analyzed compounds and reference molecule 3a, which is also an oxindole derivative with a confirmed inhibitory potential towards GSK3B protein, clearly indicates that the proposed compounds exhibit an analogous binding mechanism, and the obtained binding enthalpy values indicate a slightly higher binding potential than the reference molecule.
Keywords: GSK-3β; docking; inhibition; molecular dynamics; oxindoles.