Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

Abstract

Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators.

Discovery of Potential GSK-3β Allosteric Modulators for Alzheimer’s Disease

“…Continuing our previous work [19], we propose applying SB and LB approaches to discover new and diverse GSK-3β allosteric inhibitors. We developed two VS workflows: 1) 3D shape-based similarity plus docking, and 2) QSAR modeling using machine learning plus docking.…”

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

“…An additional class of drugs which may be worth testing in chronic malignant hematologic malignancies is represented by allosteric GSK-3 inhibitors, as they display enhanced selectivity, thereby reducing the chance of producing adverse effects [ 205 , 206 ].…”

Synthesis of Unsymmetrical Squaramides as Allosteric GSK‐3β Inhibitors Promoting β‐Catenin‐Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells

“…Besides the ATP, the substrate, and the axin/fratide binding sites, four cavities were defined as potential allosteric sites. [20] One of the cavities is situated on the Cterminal lobe of the kinase, and it is largely exposed to the solvent. Another cavity sits in the hinge region between the Cand N-terminal lobes.…”

“…All the new compounds have been synthesized through a straightforward, highly efficient, and sustainable one-pot protocol that does not employ basic catalysis and makes use of ethanol as the solvent that allowed us to collect, by filtration, the pure reaction product that precipitated off from the reaction mixture. After analyzing the GSK-3β inhibition profiles of the new compounds, the two most promising analogues 6 b and 6 j, which embed the key moieties responsible for allosteric GSK-3β inhibition, were found to be The picture was arranged to start from the PDB 1H8F and generated by PyMOL according to the findings of Silva and coworkers [19] and Palomo and collaborators [20] . Site 7 is the site previously identified by us for compound 5 (Figure 1) and the most plausible for the allosteric modulators developed in this study.…”

“…Figure 2. Schematic representation of the binding sites identified on GSK-3β.The picture was arranged to start from the PDB 1H8F and generated by PyMOL according to the findings of Silva and coworkers[19] and Palomo and collaborators[20] . Site 7 is the site previously identified by us for compound 5 (Figure1) and the most plausible for the allosteric modulators developed in this study.…”