Tipranavir is a novel non-peptidic HIV-1 protease inhibitor (PI) that has demonstrated a uniquely robust resistance profile against a large panel of isolates resistant to peptidic PI .
To explain these properties it was suggested that tipranavir binds to the active site with fewer hydrogen bonds than peptidic PI, allowing for increased flexibility to adjust to amino acid changes in the active site .
Tipranavir contains stereocentres at both C-3α and C-6 (Fig. 1). The therapeutic used isomer has the R configuration on at C-3α and C-6. Therefore, the orientation of the substituents in the active site is fixed. The X-ray crystal structure of tipranavir in complex with the active site  shows the dihydropyrone ring to be centred in the enzyme active site. The lactone oxygen atom of the ring forms hydrogen bonds with the nitrogen–hydrogen groups of the flap region isoleucine residues (Ile50/Ile50′), and the 4-hydroxy group is pseudosymmetrically bonded to the catalytic aspartate residues 25/25′. The C-6 phenethyl and propyl side chains projected into the S1′ and S2′ enzyme subsites, and the C-3α ethyl and aromatic groups occupied the S1 and S2 subsites. Tipranavir therefore has clearly defined hydrophobic binding contacts with active-site amino acids, which causes the selection of certain active-site mutations: L33F/I, V82L/T, I84V . As shown in Fig. 1 the hydrophobic interaction of the 3α ethyl group with Ile84′ leads to the selection of the I84V mutation. If the molecule is flexible in the active site, new binding contacts should lead to the selection of new mutations. But this is not the case. However, tipranavir binding in protease is less affected by these selected mutations than the binding of other PI . Therefore, tipranavir must be able to compensate for the loss of hydrophobic interactions with the mutated target.
To maintain effectiveness against resistant mutations, the strongest interaction must be directed against highly conserved residues with a very low probability of mutating .
The X-ray crystal structure  shows that tipranavir forms a hydrogen-bonding interaction with the amide backbone of active-site Asp30 (Fig. 1), which cannot be changed because of mutations at this position.
The favourable antiviral activity of tipranavir against isolates with multiple PI-associated mutations may therefore be the result of a strong hydrogen bonding interaction comparable to those of TMC-126 .
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