 A very important group on the HIV protease inhibitors is a hydroxyl group on the core motif which forms a hydrogen bond with the carboxylic acid on the Asp-25 and Asp-25´ residues in the binding site.Hydrogen bonds between the water molecule, which is linked to Ile50 and Ile50', and carbonyl groups of the peptidomimetic inhibitors seem to connect them with the flap regions.On the other hand, on the nonpeptidic inhibitors, there is a proton acceptor which replaces the tetracoordinated water molecule and interacts directly with the two Ile50 residues on the flap of the enzyme.