<unk>  is a nonpeptidic inhibitor of protease (PR) that lodges itself in the active site of PR through a number of hydrogen bonds. It was developed to increase interactions with HIV-1 protease and to be more resistant against HIV-1 protease mutations. With a Kd (dissociation constant) of 4.5 x 10−12 M,<unk>  has a much stronger interaction with PR and its dissociation constant is 1/100 to 1/1000 of other protease inhibitors. This strong interaction comes from increased hydrogen bonds between<unk>  and the backbone of the PR active site (Figure 2).<unk> 's structure allows it to create more hydrogen bonds with the PR active site than most PIs that have been developed and approved by the FDA. Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations. Because<unk>  interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation. Figure 3. Ribbon structure of PR with<unk>  in active site: Structures colored as in Fig. 1. with certain residues partaking in hydrogen bonding further highlighted. The catalytic aspartates, 25 and 25’, are in orange and the other interacting residues in green. Right image is a magnified view of the image on the left (PDB 4qdb). Catalytic site The chemical activity of the HIV-1 protease depends on two residues in the active site, Asp25 and Asp25’, one from each copy of the homodimer.<unk>  interacts with these catalytic aspartates and the backbone of the active site through hydrogen bonds, specifically binding to residues Asp25, Asp25’, Asp 29, Asp 30, Asp 30’, and Gly 27 (Figure 3). This interaction prevents viral replication, as it competitively inhibits the viral polypeptides from gaining access to the active site and strongly binds to the enzymatic portions of this protein.
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