netLibrary - eBook Summary Structure-based Drug Design by ...

Document
Page 63
most of the amino acid residues forming the pocket adjust their side chains to make close contacts with
the inhibitor, the inhibitor is not sufficient to fill all of the space in the pocket. There is space for
additional nonpolar, polar, or charged groups. Modification of the inhibitor would result in adjustment
of the orientation of the side chains and could improve interactions between the inhibitor and
surrounding residues such as Leu100, Lys101, Lys103, Val106, or Leu234. Inhibitors designed to have
more extensive interactions with essential elements in the pocket should minimize the chances of
selecting resistant HIV-1 RT variants. From this point of view, NNRTIs that interact with the relatively
conserved residues of the pocket, such as Trp229, Leu234, and Tyr318, may reduce the risk of
encountering resistance mutations that do not have significant costs for the enzyme. In addition,
compounds could be designed to contain functional groups (for example charged or polar groups) able
to fill more of the available space of the NNIBP and also capable of specific hydrophilic interactions
with the polar or charged side chains and/or with polypeptide backbone atoms of the NNIBP (for
example the main chain amide nitrogens and carbonyl oxygens). The hydrophilic interactions between
inhibitors and protein backbone atoms should be advantageous because mutations to any amino acid
other than proline would not affect such contacts. In the structures of HIV-1 RT/NNRTI complexes, the
bound inhibitors are located very close to the polymerase active site composed of the three catalytically
essential aspartic acids Asp110, Asp185, and Asp186. It might be useful to design compounds that have
a long and branched aliphatic group or a substituted aromatic group that could not only produce
hydrophobic interactions with Tyr181, Tyr188, and Trp229, but could also be able to interact with the
three aspartic residues or interfere with the metal ion(s) binding at the polymerase active site.
XI. RNase/H-Active Site as a Potential Drug Target Site
HIV-1 RT contains RNase H, which is responsible for degradation of viral RNA and removal of RNA
primers for minus- and plus-strand DNA synthesis (see reviews [87–89]). The absolute requirement for
virus-associated RNase H function [90–93] offers an additional target for antiretroviral drugs. The
RNase H domain of HIV-1 RT is located at the C-terminus of the p66 subunit (Figures 2 and 3). In
contrast to the polymerase domain of HIV-1 RT, the structure of the RNase H domain is quite similar in
all known HIV-1 RT structures and conforms quite well with the structure of the isolated HIV-1 RNase
H domain [94–95]. The relative stability of the structure of the RNase H domain suggests that the RNase
H active site could be a relatively well-defined target for drug
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_63.html [4/5/2004 4:50:40 PM]