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The mechanism(s) of resistance may depend on the specific amino acid change. It is likely that most
NNRTI-resistance mutations exert their effects by altering interactions between protein side chains and
the inhibitors [12,34,35]. Drug-resistance mutations that result in a decrease or increase in the size of
side chains might lead to loss of favorable contacts or steric conflicts with bound inhibitors. Mutations
that alter the local electrostatic potential, i.e., gain, loss, or inversion of charge, may change the affinity
of the NNIBP for inhibitor binding. These altered interactions could interfere with the binding of
NNRTIs to the hydrophobic pocket or conceivably could even relax the geometric distortion that the
binding of an inhibitor causes in the vicinity of the polymerase active site.
X. Design of Improved NNRTIs
Different NNRTIs, even from the same class of compounds, show remarkable variations in their ability
to inhibit HIV-1 replication and can give rise to different spectra of resistance mutations [9,11,26,27].
For example, biochemical studies showed that the 8-chloro TIBO derivative R86183 is quite potent in
inhibiting an HIV-1 strain containing the Tyr181Cys mutation, which is one of the frequently occurring
HIV-1 RT mutations that gives rise to a high level of resistance to almost all NNRTIs, including other
TIBO derivatives [80]. There are several other reports of NNRTIs that are also relatively effective in
inhibiting the HIV-1 RT Tyr181Cys variant [81–84]. These results suggest that although all the
inhibitors appear to bind in the NNIBP, there are differences in their specific interactions with HIV-1
RT. Structural analyses of HIV-1 RT/NNRTI complexes and computer modeling studies confirmed that
the exact conformations of the amino acid residues forming the NNIBP appear to vary in different
complexes and that there are specific interactions between individual inhibitor and surrounding residues
[33,35,36,85]. However, these differences have not been sufficiently large to allow a successful
combination therapy to be developed using two or more of the currently available NNRTIs (discussed in
more detailed in a later section) [9,11,26,27,86]. Systematic analysis of wild-type and drug-resistant
mutant HIV-1 RT structures in complexes with various NNRTIs should provide additional insights
about constraints that could be used to optimize the design of NNRTIs. This knowledge could guide
development of more effective inhibitors for AIDs treatment.
As discussed earlier, the bound NNRTIs in HIV-1 RT complexes determined so far conform to a
common butterfly-like shape (Figure 6). A close inspection of interactions between inhibitors and
protein reveals that though
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