Alchemical relative binding free energy (ΔΔ G ) calculations have shown high accuracy in predicting ligand binding affinity and have been used as important tools in computer-aided drug discovery and design. However, there has been limited research on the application of ΔΔ G methods to membrane proteins despite the fact that these proteins represent a significant proportion of drug targets, play crucial roles in biological processes, and are implicated in numerous diseases. In this study, to predict the binding affinity of ligands to G protein-coupled receptors (GPCRs), we employed two ΔΔ G calculation methods: thermodynamic integration (TI) with AMBER and the alchemical transfer method (AToM) with OpenMM. We calculated ΔΔ G values for 53 transformations involving four class A GPCRs and evaluated the performance of AMBER-TI and AToM-OpenMM. In addition, we conducted tests using different numbers of windows and varying simulation times to achieve reliable ΔΔ G results and to optimize resource utilization. Overall, both AMBER-TI and AToM-OpenMM show good agreement with the experimental data. Our results validate the applicability of AMBER-TI and AToM-OpenMM for optimization of lead compounds targeting membrane proteins.