All the HIV protease inhibitors on the market contain a central core motif consisting of a hydroxyethylen scaffold, with the only exception being the central core of tipranavir, which is based on a coumarin scaffold.  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. Specific pockets in the binding site of the HIV protease, often referred to as S1, S1,S2 and S2', recognize hydrophobic amino acids on natural substrates. The potency of inhibitors bearing hydrophobic groups complementing these areas is therefore increased. Some residues in the enzyme binding site are capable of forming hydrogen bonds with hydrophilic groups on the inhibitor, for example with the THF moieties on amprenavir and darunavir. Since darunavir has a bis-THF moiety, instead of a single THF moiety like on amprenavir, it can form more hydrogen bonds and increase binding energy.