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It is also attractive to consider developing agents that bind to the HIV-1 RT polymerase active site but
are not nucleoside analogs. Since the amino acid residues at the dNTP-binding site are highly conserved,
viral variants resistant to such inhibitors may be significantly impaired in their polymerase activity.
However, there is a good chance that drug resistance could result from mutations in HIV-1 RT that
influence the precise positioning of template-primer [54]. Initial attempts to use this approach starting
from the crystal structure of the HIV-1 RT/DNA/Fab complex [38] (Ding, et al., in preparation) have
uncovered some interesting lead compounds (Kuntz, Kenyon, Arnold, Hughes, et al., unpublished).
VI. NNRTIs and the NNIBP
Nonnucleoside RT inhibitors (NNRTIs) constitute the other major class of HIV-1 RT inhibitors. Many
structurally distinct families of NNRTIs have been identified, including HEPT [13], TIBO [14],
nevirapine [15], BHAP [17], TBA [18,19], TSAO [76], α-APA [21], pyridinones [16] and quinoxalines
(HBY) [22,23] (Figure 1b). However, development of drug resistance is a major problem when NNRTIs
are used to treat AIDS patients. An ideal drug should be able to block replication of all viable strains of
HIV-1, but should not inhibit normal cellular enzymes. In this regard, the known NNRTIs may be too
specific. While these inhibitors do not inhibit cellular polymerases, they are also inactive against HIV-2
RT (which can be viewed as an extreme variant of HIV-1 RT). In addition, drug-resistant variants of
HIV-1 RT emerge rapidly in the presence of most inhibitors. In contrast, the NRTIs inhibit a broad
spectrum of polymerases including the host cellular polymerases. Though it appears to be more difficult
for the virus to evade NRTIs than NNRTIs (in general, it takes longer for the virus to develop resistance
to NRTIs than NNRTIs), NRTI toxicity is a serious problem.
Structural and biochemical studies have shown that all NNRTIs bind in a highly hydrophobic pocket in
the p66 subunit, located approximately 10 Å away from the polymerase active site (Figures 2 and 3)
[31,33–37]. Nevertheless, in all known structures of HIV-1 RT/NNRTI complexes, the bound NNRTIs
have not been found to have any direct interactions with residues that compose the putative dNTPbinding
site. The nonnucleoside inhibitor binding pocket (NNIBP) contains primarily amino acid
residues from the β5–β6 loop (Pro95, Leu100, Lys101, and Lys103), β6 (Val106 and Val108), the
β9–β10 hairpin (Val179, Tyr181, Tyr188, and Gly190), and the β12–β13 hairpin (Phe227, Trp229,
Leu234, His235, and Pro236) of the p66 palm subdomain, and β15 (Tyr318) of the p66 thumb
subdomain, as well as the β7–β8 connecting loop (Glu138) of the p51 fingers subdomain (Figure 6 and
Table 3).
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