The Oxindole Derivatives, New Promising GSK-3β Inhibitors as One of the Potential Treatments for Alzheimer’s Disease—A Molecular Dynamics Approach

SIMPLE SUMMARY: Enzymatic overexpression is a determinant of the development of many diseases. Increased activity of the GSK-3β enzyme is a factor that manifests itself in the development of numerous disease entities such as Alzheimer’s disease, schizophrenia, diabetes and cancers. An important medical procedure in such cases is the inhibition of enzyme activity. Based on the comprehensive use of computational chemistry methods, a group of new compounds derived from 2-oxindole was designed. The conducted research allowed the assessment of the conformational properties of the ligand molecules in the GSK-3β active site, the dynamic stability of the obtained complexes and their exact energetic characteristics. Taking into account the obtained data, a narrow group of derivatives showing an affinity for the active site of the GSK-3β enzyme was selected. The comparison of binding properties of selected 2-oxindole derivatives with an inhibitor with confirmed pharmacological activity indicates the high application potential of the newly developed compounds. ABSTRACT: 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.