The affinity of drug molecules to their respective molecular targets can be described by the thermodynamic properties of the molecular interaction. These properties typically reflect the totality of all underlying molecular recognition processes during ligand binding and are defined by a complex mix of many contributions. This is a direct consequence of not following a simple rigid two-body lock-and-key interaction model but rather going through a highly dynamic process including changes in protein and/or ligand flexibility as well as solvation and desolvation effects. Notwithstanding this known complexity, consulting thermodynamic signatures had been proposed as means to select and/or design drug molecules that offer an accelerated path for further development [1]. Whilst initially providing a more advanced concept for increasing the success in prospective drug design, it has come lately under scrutiny due to lack of the envisioned impact in drug discovery [2]. A major factor that impacted negatively on the utility of thermodynamic signatures is their strong and unpredictable modulation by the local water structure. Although providing a challenge, this also displays a large untapped potential for drug discovery, as weve lately gained much more thermodynamic and structural insights into the role of water molecules for ligand binding.