The prevailing methods for computing ABFE mainly rely on free energy perturbation (FEP) and thermodynamic integration (TI), both of which require extensive sampling in the configurational space . Thus, in ture, demands substantial computational resources and time. Alternatively, endpoint methods, such as MM/PBSA or MM/GBSA, can approximate ABFE by calculating the free energy difference between the bound and unbound states of solvated molecules, which significantly reduces computational demands but at the expense of accuracy . Balancing computational resource consumption and calculation accuracy remains a perennial challenge, significantly limiting the practicality of ABFE calculations .