A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3 beta). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3 beta through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent contact model, we identified several GSK3 beta inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (12 and 27) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3 beta because of the high specificity for the inhibition of GSK3 beta