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of the active-site aspartates. Similar to Ag1002 and other peptidic inhibitors, the carbonyl oxygens of the
P2 and P1' amides are within hydrogen-bonding distance of the flap water molecule; however, the
geometry of the second hydrogen bond is distorted due to the additional spacing between both carbonyl
groups. The nitrogen of the t-butylamide is displaced from the normal P2' position by approximately 1.8
Å and, as a result, cannot form a direct hydrogen bond with the carbonyl oxygen of Gly27. Instead the tbutylamide
nitrogen interacts via highly ordered water molecules with the amide nitrogen of Asp29 and
the carbonyl oxygen of Gly27. The aliphatic t-butyl moiety occupies the S2' subsite and the position of
the backbone in this region prohibits any further extension into the S3' pocket. The P1 and P2 side
chains of phenylalanine and asparagine, respectively, occupy the corresponding subsites and have a
similar conformation to the equivalent groups observed in peptidic inhibitors. In the crystal structure, the
N-terminal quinoline-2-carboxylate is moved to the side and, as a result, the carbonyl oxygen forms
hydrogen bonds with the ordered water molecule and with the amide nitrogen of Asp29'. The quinoline
ring is in a low-energy conformation with respect to the preceding carbonyl oxygen, which places the
aromatic nitrogen in unfavorable close contact (3.3 Å) to the carbonyl oxygen of the flap Gly48.
Because of the absence of any further contacts with the HIV PR active site residues, the contribution of
the quinoline moiety to the free energy of binding remains unclear. Perhaps in solution, a stacking
interaction of the P1 phenyl ring and the aromatic quinoline restricts the conformational freedom of Ro-
31-8959, in effect diminishing the free-energy loss due to the entropic and desolvation effects.
Saquinavir, despite its distinct peptidomimetic character is a very potent inhibitor of HIV PR with an
inhibition constant of 0.9 nM and an antiviral IC50 in vitro of 0.020 μM [10]. Although it suffers from a
low oral bioavailability (5–10% in humans), it became an important starting point for the design of
second generation, less-or nonpeptidic inhibitors. Saquinavir became the first HIV PR inhibitor
approved by the FDA for treatment of AIDS.
Design and Structure of ABT-538 (Ritonavir)
An interesting concept for designing specific HIV PR peptidomimetic inhibitors with internal two-fold
symmetry was first formulated by John Erickson and his colleagues from Abbott Laboratories [28].
They reasoned that if HIV PR incorporates symmetry into its active site structure, compounds that
mimic this symmetry might be novel, more specific, and potent inhibitors and, furthermore, due to the
bidirectionality of peptide bonds, might be sufficiently less peptidic in character and pharmacologically
superior to the classical peptide-based compounds. The crystal structure of one of the first compounds
from this series (A74704) verified the assumption of symmetrical binding conformation in the
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