Protein-ligand binding affinity calculation has drawn a lot of attention for many years because of its ability to significantly accelerate drug discovery by focusing experimental effort on high quality leads. Using molecular dynamics (MD) or Monte Carlo algorithms to perform the necessary sampling, many methods have been developed to address this task : These include the linear interaction energy (LIE) approach , the Molecular Mechanics-Poisson-Boltzmann/Surface Area (MM-PBSA) and Molecular Mechanics-Generalized Born/Surface Area (MM-GBSA) approaches, and physical pathway methods such as the Umbrella Sampling (US) method combined with Weighted Histogram Analysis (WHAM) or variational free energy profile (vFEP) methods .