Recently, the core hopping FEP method has successfully conducted RBFE calculations for minor and limited scaffold hopping cases. However, most scaffold hopping procedures typically involve substantial topology changes of the entire ligand. To accurately predict the binding free energies of ligands following scaffold hopping, it is essential to use ABFE calculations rather than RBFE calculations. In 2022, Wu et al. utilized ABFE calculations to guide scaffold hopping in the design of PDE5 inhibitors. Following their reported procedure, we used Glide to dock L1 to the crystal structure of PDE5-tadalafil (PDB ID: 1XOZ) and to dock L2 to L12 to the crystal structure of PDE5-L1 (PDB ID: 7FAQ). The LumiNet model was then used to performed ABFE predictions in a zeroshot setting. Notably, compounds L1 to L12 were designed based on tadalafil and LW1607, with significant structural differences from their initial structures.