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V. Drug Design Targeting at the Polymerase Active Site
Page 55
All of the existing NRTIs contain a modified sugar moiety that lacks the 3'-OH group that is essential
for incorporation of the next nucleotide. Modification can also be made on other functional groups such
as the base and the triphosphate moieties. It may be worthwhile to try to alter the base moiety of the
NRTIs to produce compounds that will be more specific to HIV-1 RT (i.e., less cytotoxic to normal
cellular polymerases) and more effective against both wild-type or drug-resistant viral variants.
Structure-activity analysis indicates that the pyrimidine moiety of the NRTIs can be modified at the C5
position. An AZT derivative that has a 3'-azido group on the sugar moiety and a methyl group at the C5
position of the pyrimidine moiety showed potent antiviral activity [65]. Substitution of the methyl group
with a chlorine atom at position C5 of AZT results in a compound that has strong anti-HIV-1 activity
[66]. Other possible substitutions at the C5 position include other halogen atoms or an ethyl group.
Another possible drug-design strategy would be to devise compounds that can interface with the binding
of the metal ions (Mg 2+ or Mn 2+) at the polymerase active site. Metal ions appear to be important in
DNA polymerase catalysis. Based on the structural and biochemical data, a two-metal dependent
mechanism of polymerization has been postulated [53,67,68] that is similar to that proposed for other
DNA polymerases [69–71]. In this model, the metal ions mediate interactions between the three
catalytically essential aspartic acid residues (Asp100, Asp185, and Asp186) and the α-, β-, and γphosphates
of the incoming dNTP and promote the nucleophilic attack on the α-phosphate by the
oxygen atom of the 3'-OH group of the primer strand. In the structure of the fingers and palm
subdomains of the RT of Moloney murine leukemia virus (MuLV), a single Mn 2+ ion was found bound
to the two aspartic acid residues at the polymerase active site [72]. In the structure of the unliganded
HIV-1 RT, an electron density peak was located at the polymerase active site with a good coordination
geometry to the Oδ1 atoms of both Asp185 and Asp186 [43]. This electron-density peak is in a position
similar to that of the Mn 2+ ion observed in the MuLV RT structure. It is possible that this position
corresponds to a Mg 2+ ion-binding site [43]. It might be useful to design inhibitors that would influence
the metal-ion coordination using either computer-based calculations (such as DOCK [73–75]) or based
directly on an analysis of HIV-1 RT structure. Crystal structures of HIV-1 RT complexed with
Mg 2+/Mn 2+ ion(s) at the polymerase catalytic site in the presence of template-primer and/or dNTP
substrates would be helpful in defining the target sites of inhibitors of this type. Further studies on the
structure activity relationship of HIV-1 RT complexes with these inhibitors, if active, might ultimately
lead to a new type of HIV-1 RT drug that would not compete with the dNTP binding but would affect
the DNA polymerization mechanism.
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