Integrated 3D-QSAR and Docking Study of Alkylpiperazine-Based GSK-3β Inhibitors

Glycogen synthase kinase-3β (GSK-3β), a protein kinase with diverse roles in various biological processes, has emerged as a promising target for drug research in the treatment of numerous clinical diseases. In this study, we employed a combination of computational techniques, including molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR), to investigate a set of 36 alkylpiperazine derivatives as potential GSK-3β inhibitors. Our best-performing 3D-QSAR model yielded impressive conventional determination coefficients R2 of 0.95 and leave-one-out cross-validation Q2 of 0.56, showcasing its robustness and predictive capability. External validation using a test set of six compounds further confirmed the model's reliability, with anticipated R2test values of 0.87. To reinforce the validity of our 3D-QSAR model, a Y-Randomization test was conducted. Additionally, to investigate the binding interactions between the most active chemical and the GSK-3β protein's active site (Protein Data Base ID: 1Q4L, we used molecular docking simulations. These docking results not only corroborated the findings from our 3D-QSAR analysis but also provided valuable insights into the binding mode of alkylpiperazine derivatives with GSK-3β. These results are very interesting, and they help us understand how alkylpiperazine compounds interact with GSK-3β. This information is important for creating new and strong GSK-3β inhibitors. These inhibitors could be used to treat different diseases.