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line moiety, and the N-terminal benzyloxycarbonyl group was replaced by the quinoline-2-carbonyl. The
resulting compound, Ro-31-8959, was one of the first peptidomimetic inhibitors with very high antiviral
potency and became a benchmark for further design of HIV PR inhibitors [10].
The high-resolution crystal structure of saquinavir bound to the active site of HIV PR was solved in
many laboratories [23,27]. The incorporation of decahydroisoquinoline moiety, which can be considered
as a conformationally restrained mimic of cyclohexylalanine, has some important consequences. First,
the length of the C-terminal part of the inhibitor has been restricted to the P2' residue which, in
saquinavir, consists of a NH-t-butyl group. Second, it restrained the conformational freedom of the
otherwise peptidic backbone, minimizing the entropic penalty to the free energy of binding. In the
crystal structure of saquinavir with HIV PR (Figure 4), the decahydroisoquinoline in the preferred chairchair
conformation, makes extended hydrophobic contacts in the S1' subsite. The bond between the
methylene carbon and the nitrogen of decahydroisoquinoline is in the low-energy equatorial
conformation and the nitrogen, even if protonated, is not in a position to form a hydrogen bond with the
active-site residues. The central hydroxyl group is in the R(syn) conformation and is within the
hydrogen-bond-forming distance with both carboxylates
12640-0012a.gif
Figure 4
Stereo view of the peptidomimetic inhibitor Ro 31-8959 (saquinavir) bound
to the active site of HIV PR. The distribution of the specificity subsites S and
S' is identical to that shown in Figure 2. Note the stacking interaction
between the quinoline moiety and the P1 side chain of phenylalanine.
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