Knowledge of hydration and the role of solvent in protein–ligand (P-L) binding is essential for rational drug design. In this direction, a complete description of P-L binding requires a clear understanding of the change in protein and ligand hydration states when they form a complex. In the present work, we investigated the 3D-hydration of protein tyrosine phosphatase 1B (PTP1B) in the unbound and bound states and changes in this process occurring upon the complex formation with 2HB1 and 2QBP inhibitors as an example. To this end, we have used a simplified version of the site density functional theory - the three-dimensional reference interaction site model. The obtained data indicate that both the ligands and PTP1B in unbound state are well-hydrated. Upon complex formation, the ligands experience significant dehydration, while the level of PTP1B hydration changes little. Moreover, the hydrated state of P-L complex remains practically the same as for liganded PTP1B itself. In this case, some of the waters are partly “collectivized” by the protein and the ligand, i.e., solvent molecules will be shared by PTP1B and 2HB1/2QBP. The active site pocket of the protein was also found to be well-hydrated. P–L binding results in partial dehydration of the pocket, which is connected with the displacement of part of the water from the pocket by the ligand. The results show the presence of two/seven waters inside the pocket for PTP1B-2HB1/2QBP. Location of the most tightly bound two/three waters in the PTP1B-2HB1/2QBP complex is coinsiding with the PDB data. Among tightly bound waters, only two molecules are “bridging” ones, i.e., forming simultaneously H-bonds with pocket residues and ligands. In addition, all possible H-bonds between the ligand, pocket amino acid residues and water are discussed for both complexes. The data obtained are necessary for understanding the molecular mechanisms of the PTP1B functioning and the creation of selective regulators of its activity.
