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inhibitor form 16 hydrogen bonds and occupy subsites from S4 to S1, S2', and S3'. The carbonyl
oxygens of P2 and P1' accept two hydrogen bonds from the flap water Wat301, which in effect is nearly
tetrahedrally coordinated. Due to the structural nature of statine, which lacks the P1' side chain, the S1'
pocket remains unoccupied. The S1 subsite is only partially filled by the P1 side chain of leucine. The
P2 and P2' side chains of asparagine and glutamine form hydrogen bonds with Asp30' and 30, while the
aliphatic carbons of both side chains make several hydrophobic contacts in the S2 and S2' pockets
respectively. Despite the large number of hydrogen bonds formed within the HIV PR active site,
AG1002 has rather low inhibitory potency with a binding constant of 0.55 μM The low binding constant
most likely reflects the absence of the P1' group, the free energy required for desolvation of the
hydrophilic side chains, and the charged N- and C-termini as well as entropic effects caused by the
flexible nature of the heptapeptide.
Other interesting examples of peptidic inhibitors are compounds utilizing other transition-state analogs,
e.g. reduced amide-containing hexapeptide MVT-101 [24], hydroxyethylene-containing octapeptide U-
85548e [25], and hydroxyethylamine-containing heptapeptide JG-365 [26]. All these compounds bind to
the active site of HIV PR in a similar extended conformation and the small differences in the geometry
of hydrogen bonds formed with HIV PR can be attributed to the different character and length of the
transition-state analogs. The chemical structures and inhibition constants of these inhibitors are
summarized in Table 2. Note that the inhibition constants cited throughout this chapter and in Tables 2,
3, and 6 were determined in different laboratories—often using significantly different assay
conditions—and therefore might not be meaningfully comparable.
Due to their substantial size and peptidic nature, inhibitors from this class were not suitable for clinical
application. Nevertheless, the structural information derived from many crystal structures of peptidic
inhibitors bound to the HIV PR active site was critical for subsequent modeling and design of the next
generation of peptidomimetic and nonpeptidic inhibitors of HIV PR.
E. Peptidomimetic Inhibitors of HIV PR
Design and Structure of Ro-31-8959 (Saquinavir)
The strategy of designing saquinavir was based on the transition-state mimetic concept, an approach that
has been used successfully in the design of potent inhibitors of renin and other aspartic proteases [10].
From the variety of nonscissile transition-state analogs of a dipeptide, the hydroxyethylamine mimetic
was selected because it most readily accommodates the amino acid moiety characteristic of the Phe-Pro
and Tyr-Pro cleavage sequence of the
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