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

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.