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Accurate and reliable calculation of protein–ligand binding affinities remains a hotbed of computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in drug design projects, practical applications of FEP in industrial contexts have been limited. In this work, we use a recently developed method, FEP/REST (free energy perturbation/replica exchange with solute tempering), to calculate the relative binding affinities for a set of congeneric ligands binding to the CDK2 receptor. We compare the FEP/REST results with traditional FEP/MD (molecular dynamics) results and MM/GBSA (molecular mechanics/Generalized Born Surface Area model) results and examine why FEP/REST performed notably better than these other methods, as well as why certain ligand mutations lead to large increases of the binding affinity while others do not. We also introduce a …