Water molecules in the active site of an enzyme occupy a complex, heterogeneous environment, and the thermodynamic properties of active-site water are functions of position. As a consequence, it is thought that an enzyme inhibitor can gain affinity by extending into a region occupied by unfavorable water or lose affinity by displacing water from a region where it was relatively stable. Recent advances in the characterization of binding-site water, based on the analysis of molecular simulations with explicit water molecules, have focused largely on simplified representations of water as occupying well-defined hydration sites. Our grid-based treatment of hydration, GIST, offers a more complete picture of the complex distributions of water properties, but it has not yet been applied to proteins. This first application of GIST to protein–ligand modeling, for the case of Coagulation Factor Xa, shows that ligand scoring functions based on GIST perform at least as well as scoring functions based on a hydration-site approach (HSA), when applied to exactly the same simulation data. Interestingly, the displacement of energetically unfavorable water emerges as the dominant factor in the fitted scoring functions, for both GIST and HSA methods, while water entropy plays a secondary role, at least in the present context.