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inhibitors 100 [157] and 101 [158]; the nonsymmetric peptidomimetics 44 [50] and 102–106 [159–163,
respectively]; and a series of nonpeptides derived originally from either 3-D computational searching
107 [164] or high-throughput sceening 108–110 [165–168], respectively. Of these compounds, FDA
approval has been recently granted to 102 (Indinivar), 103 (Ritonavir), and 44 (Saquinavir).
Currently, it is believed that there exists well over 150 x-ray crystallographic structures of HIV proteaseinhibitor
complexes, not including mutated forms of the target enzyme that have also been determined to
be important to develop inhibitors which will be effective in so-called HIV resistant strains. The initial
series of x-ray crystallographic structures of HIV protease included the apoprotein [169] and enzymeinhibitor
complexes derived from substrate-based analogues having P 1-P 1' substitutions by
N1eΨ[CH 2NH]N1e [170], LeuΨ[CH(OH)CH 2]Val [171], PheΨ[CH(OH)CH 2N]Pro [172], and
LeuΨ[CH(OH)]Gly or statine [173]. As illustrated in Figure 24, the first reported HIV protease-inhibitor
complex [170] with the pseudopeptide 111 provided a high-resolution map of the active site of the
enzyme as formed in a C 2-symmetric fashion by the homodimer, and the “flaps” of each monomeric
subunit (i.e., residues 35–57) were shown to make intermolecular interactions with the backbone of the
inhibitor by both direct hydrogen-bonding and through a structural water molecule (W301). Relative to
the C 2-symmetry of the target enzyme, the discovery of C 2-symmetric inhibitors was successfully
achieved by the design of PheΨ[CH(OH)]gPhe- and PheΨ[CH(OH)CH(OH)]gPhe-modified
peptidomimetics (gPhe refers to gem-diamino-Phe in which the Cα-CO 2H moiety is replaced by Cα-
NH 2) as exemplified by 101 [157] Among the plethora of other structure-based drug design strategies
focused on HIV protease inhibitor discovery it is also noteworthy to highlight the nonpeptide leads 100
and 108–111 as they displace a key structural water (i.e., W301) and, as opposed to all previously
discovered substrate-based inhibitors, are capable of direct hydrogen-bonding interactions to the HIV
protease flap regions (Figure 24). These discoveries provide impetus for molecular design strategies to
consider tightly bound water molecules as possible secondary “ligands” in either de novo design or
iterative structure-based design of novel peptidomimetic or nonpeptide lead compounds. Previous
studies [174] on biotinstrepavidin and an x-ray crystallographic structure of the complex showed that
structural water molecule displacement (relative to the apoprotein) by key functional groups of the
ligand (biotin) was possible. It is noted, however, that HIV protease is unique from other members of the
aspartyl protease family with respect to the role of structural water W301 role in substrate/ inhibitor
binding. The catalytic water, which is critical to the mechanism of substrate cleavage for all aspartyl
proteases, has been a key feature in the design of a plethora of so-called “transition state” modified
inhibitors that incorporate a tetrahedral
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