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volume of the active site. With this in mind, the dimethylbenzyl group was attached to compound III and
the additional phenyl ring was accommodated well in the lipophilic pocket of the S1'/S3' sides. As the
S1 pocket was not fully occupied, a Monte Carlo-based De Novo Ligand-Generating program
(MCDNLG) [46] was used to identify other amide substituents that might fill this subsite more
effectively. From several moieties identified by the MCDNLG program, a larger cyclopentylethyl group
showing very good shape complementarity to the S1/S3 subsite was selected for synthesis. In addition,
due to the asymmetrical nature of this compound, additional space was identified at the bottom of the
S2' pocket that was conveniently filled with either a methyl or a chlorine group on the 5 position of the
benzamidine ring. The inhibition constant of the resulting compound (compound IV in the Table 6) was
0.008 μM, which represents approximately a 2500-fold improvement over the first compound from this
series.
The crystal structure of compound IV or AG1284 complexed with HIV-1 PR was solved, revealing
excellent complementarity between the ligand and protein. The ligand forms only 4 hydrogen bonds
with either protein functional groups or ordered water molecules, in contrast to the nine hydrogen bonds
formed by peptidomimetic LY289612, despite their similar binding affinities. The nonpeptidic character
of AG1284 may have contributed to good oral bioavailability and pharmacokinetics in three animal
species [43].
Despite very good inhibitory potency on the enzyme level, AG1284 has rather modest antiviral activity
in vitro (Table 6). The reason for this discrepancy is unclear but could be related to the low water
solubility and higher affinity for membranes, which may effect cell partitioning. A similar lack of
correlation between the potency of enzyme inhibition and antiviral activity has been previously observed
with other HIV PR inhibitors [11].
Hydroxypyrans and Hydroxycoumarins
The lead compounds for the 4-hydroxypyran and 4-hydroxycoumarin series were discovered in
biological screens as low potency inhibitors of HIV PR [47–49]. Successful structure solution of both
lead compounds with HIV PR enabled rapid optimization of their enzyme inhibitory potencies and anti-
HIV activities, and one of these compounds, U96988, has already entered Phase I clinical testing
[49,50]. The binding mode of this type of inhibitor differs substantially from the classical
peptidomimetic compounds and is somewhat similar to de novo-designed compounds from the cyclic
urea series. In the case of 4-hydroxycoumarin, the two oxygen atoms of the lactone functionality are
positioned within hydrogen-bonding distance of the two NH amides of Ile50/50' on the flap, replacing
the ubiquitous water molecule Wat301. The 4-hydroxyl group (Table 5) is located within hydrogenbonding
distance of the two catalytic
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