Water plays a crucial role in all biological processes due to its peculiar physical and chemical properties. It represents not only the environment for biochemical reactions but is also an active participant. Without a critical level of hydration proteins are inactive and the presence of water molecules is essential in the catalytic sites of many enzymes. From a thermodynamic point of view, water molecules can favorably contribute to the formation of protein complexes. It is, therefore, reasonable to assume that not all water molecules in contact with a protein have the same propensity for displacement by a ligand. In this work we suggest a new approach for the analysis of the entropy of water molecules by evaluating the variability of H-bond networks in the hydration shell. This type of approach has proved to be effective in improving the prediction of binding energy between receptor and ligand and has also allowed to identify new possible binding sites. The results are in accordance and expand the basic idea that binding sites often lies on conserved regions.