A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β

We propose a novel cheminformatics approach that combines structure and ligand-based design to identify target-specific pharmacophores with well-defined exclusion ability. Our strategy includes the prediction of selective interactions, developing structure, and knowledge-based selective pharmacophore models, followed by database screening and molecular docking. This unique strategy was employed in addressing the off-target toxicity of Gsk3β and CDKs. The connections of Gsk3β in eukaryotic cell apoptosis and the extensive potency of Gsk3β inhibitors to block cell death have made it a potential drug-discovery target for many grievous human disorders. Gsk3β is phylogenetically very closely related to the CDKs, such as CDK1 and CDK2, which are suggested to be the off-target proteins of Gsk3β inhibitors. Here, we have employed novel computational approaches in designing the ligand candidates that are potentially inhibitory against Gsk3β, with well-defined the exclusion ability to CDKs. A structure-ligand -based selective pharmacophore was modeled. This model was used to retrieve molecules from the zinc database. The hits retrieved were further screened by molecular docking and protein–ligand interaction fingerprints. Based on these results, four molecules were predicted as selective Gsk3β antagonists. It is anticipated that this unique approach can be extended to investigate any protein–ligand specificity.