The first day of ACTC focused heavily on the biological aspects of theoretical chemistry, especially protein folding and protein-ligand binding affinities. Richard Friesner gave a particularly interesting talk exploring the methodology of drug discovery and the use of a tool he designed called WaterMap. WaterMap examines the thermodynamic properties of clusters of water molecules and classifies them according to their stability with respect to bulk solution. With such a map, pharmaceutical researchers can design compounds to knock out unstable waters upon binding while minimizing interactions with stable water clusters.
An example where this would have been extremely helpful is in the design of Factor 10a, an anticoagulant. Factor 10a binds in two main cavities, and WaterMap reveals that each cavity has one very unstable water. Unfortunately, WaterMap was not used during the design of this drug. Thus, for fifteen years it was unknown that all of the different compounds being tested successfully displaced one of the unstable waters while the other water was untouched. It wasn’t until 1999, twenty years after the research began that an accidentally placed benzene with a para Cl successfully knocked out the second water and lead to a successful drug.