Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.