Alzheimers disease (AD) is a multifactorial neurodegenerative disorder with several targets contributing to its aetiology.Despite of the devastating effects of this disease, therapeutic methods for treating AD remain limited.The notion of one molecule-one target-one disease has been a prevalent paradigm in medical treatment However, nowadays, design of multiple-target structures determines recent studies of developing novel drugs.The multifactorial nature of AD strongly supports the rationale for a drug design strategy centered on multi-target.Progress in understanding the molecular biology of AD has provided a relevant number of therapeutic targets for disease-modifying interventions.Protein kinases have been identified to contribute to the neuronal decay with GSK-3β and CDK5 being involved in a pathological tau-protein hyperphosphorylation, which leads to the formation of neurofibrillary tangles.In this study, using the virtual screening method, we screened out eleven novel structures simultaneously inhibit GSK-3β and CDK5 as top-leads for the treatment of AD.The docking poses were identified using Discovery Studio Visualizer 3.5.The docking results showed that the inhibitors interacted with residues in both the substrate binding site of GSK-3β and CDK5.Docking a test set of actives, we found the enrichment study showed that the docking model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening.Furthermore, optimization studies were performed for eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of GSK-3β and CDK5.These results could be valuable for the discovery and development of specific dual GSK-3β/CDK5 inhibitors.