Mapping Water Thermodynamics on Drug Candidates via Molecular Building Blocks: a Strategy to Improve Ligand Design...

The consideration of interactions involving water molecules in protein-ligand binding is widely appreciated in drug discovery nowadays. However, it is not ultimately clear how insights about these interactions translate into molecular design concepts. In this work, we introduce a computational strategy that, trained with high-precision experimental data, allows for the decomposition of water-related thermodynamic properties into chemically relevant building blocks (BBs) of a given ligand scaffold. For each of these BBs, a score based on solvation energy and entropy is computed, thus enabling the analysis of solvent-related affinity contributions for individual BBs. We find the nonvariable BB in a congeneric ligand pair to have a larger impact on the binding affinity than the variable part thus suggesting strong cooperative effects. Furthermore, we find enhanced solute-solvent interactions for a BB due to the presence of a C-F bond. Our investigation may be used to design drug molecules with tailored solvent thermodynamic properties.