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water mimic was used and in subsequent synthetic targets the cyclohexanone ring was enlarged to a 7membered
ring to incorporate a diol functionality. This target was further modified to a cyclic urea,
which can be symmetrically substituted from both nitrogens without creating unnecessary stereocenters.
The crystal structures of about 10 cyclic-urea-based inhibitors with HIV PR were solved [42]. In all
cases, the C2 symmetric inhibitors bind to the HIV PR active site with the diad symmetry axes of the
protease and the compounds being nearly coincident. The 7-membered ring of the inhibitors is roughly
perpendicular to the plane of the catalytic aspartates 25/25' and both hydroxyl groups of the diol are
positioned to interact with their carboxylates. The carbonyl oxygen of the inhibitors accepts hydrogen
bonds from backbone amides of symmetrically distributed residues Ile50/50' of the flap. In the structure
of DMP323, symmetrically substituted moieties of hydroxymethylbenzyls and phenylalanines extend
towards the S2/S2' and S1/S1' subsites respectively and are involved in van der Waals interactions with
the hydrophobic residues of these pockets [42].
The interaction of DMP323 with the residues of HIV PR are restricted to the central four specificity
subsites of the active site. Despite this limited area of hydrophobic interaction and hydrogen bonding
restricted to the central cyclic urea functionality, DMP323 is a very potent inhibitor of HIV PR with
good antiviral activity in vitro (Table 5). The limited solubility of this compound was perhaps
responsible for erratic oral availability in humans, and after short trials, DMP323 was withdrawn from
the clinical investigation. Nevertheless, the discovery of this class of compounds represents a very
interesting and, by now, classical example of de novo structure-based drug design.
Design and Structure of AG1284
Another compound discovered by the application of de novo structure-based design is AG1284 [43]. In
the initial design of a lead compound, the nonpeptidic hydroxyethyl-t-butylbenzylamide portion of
LY289612 occupying the S1' and S2' subsites was retained as a “starting module.” In attempting to fill
the pockets related by the dimer two-fold symmetry it was discovered that, by extending a two-carbon
fragment from the central hydroxyl carbon, the S1 subsite could be accessed by an aromatic ring. The
ring was oriented orthogonal to the observed P1 phenyl group of the classical inhibitors and this allowed
further extension off the ortho position towards the S2 subsite. In order to maintain the critical hydrogen
bond to the flap water Wat301, in the initial compounds an acylated amino group was used, replaced in
subsequent designs by a benzamide functionality. In this model, the geometry of the hydrogen bonds to
the flap water was somewhat perturbed, and the nitrogens of the t-butyl amides on both sides of the
compound were in a position to interact favorably with solvent,
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