The analysis of a crystal structure active site can greatly aid the design of small molecules. By understanding what water does in an active site, conclusions can be drawn about what ligands should be doing. OpenEye’s SZMAP software analyzes sites using semi-continuum solvation theory, which combines single explicit probe water with Poisson-Boltzmann continuum theory. By sampling various orientations of the water molecule, SZMAP can estimate thermodynamic properties useful in understanding the solvent role in ligand binding. While SZMAP can explore any part of an active site, an additional tool called GamePlan is more focused on modifications on a ligand. It explores the region immediately around a ligand and produces hypotheses for ways to optimize the ligand. Both applications will be introduced in the webinar with practical examples of how both tools can be used.