This thesis explores the use of cell theory calculations to characterise hydration thermodynamics
in small molecules (cations, ions, hydrophobic molecules), proteins and
protein-ligand complexes. Cell theory uses the average energies, forces and torques of
a water molecule measured in its molecular frame of reference to parameterise a harmonic
potential. From this harmonic potential analytical expressions for entropies and
enthalpies are derived. In order to spatially resolve these thermodynamic quantities
grid points are used to store the forces, torques, and energies of nearby waters which
giving rise to the new grid cell theory (GCT) model. GCT allows one to monitor hydration
thermodynamics at heterogeneous environments such as that of a protein surface.
Through an understanding of the hydration thermodynamics around the protein and
particularly around binding sites, robust protein-ligand scoring functions are created to
estimate and rank protein-ligand binding affinities. GCT was then able to retrospectively
rationalise the structure activity relationships made during lead optimisation of
various ligand-protein systems including Hsp90, FXa, scytalone dehydratase among
others. As well as this it was also used to analyse water behaviour in various protein
environments with a dataset of 17 proteins. The grid cell theory implementation provides
a theoretical framework which can aid the iterative design of ligands during the
drug discovery and lead optimisation processes, and can provide insight into the effect
of protein environment to hydration thermodynamics in general
