Structural Analysis of HIV‑1 RNase H Bound to a Galloyl Active Site Inhibitor and Computational Compound Modification

The emergence of drug-resistant viruses is a significant
concern
for the treatment of human immunodeficiency virus type-1 (HIV-1) infection,
despite the availability of various drugs that block viral replication
and propagation. Drugs that act upon unexploited targets of the viral
replicative cycle may be able to circumvent resistance. The RNase
H activity of HIV-1 reverse transcriptase is a viral enzymatic function
for which no approved inhibitors are available. The active site of
RNase H contains two metal cations that are required for catalysis.
In this study, we describe the X-ray crystal structure of p15Ec (an
HIV-1 RNase H domain recombinant protein) bound to an active-site
inhibitor containing a pyrogallol moiety with chelating properties.
The analysis revealed three hydroxyl oxygen atoms on the pyrogallol
that firmly chelate two metal ions at the catalytic site. Molecular
mechanics (MM) calculations were performed to determine the contributions
of the respective compound atoms to the binding score. The analysis
suggested that a piperazine moiety connected to the pyrogallol was
not required to interact with the RNase H domain. A total of 6,757
derivatives were generated by replacing piperazine with other chemical
groups. This was reduced to 5,567 following optimization of their
binding poses by MM calculations, which indicated that the pyrogallol
moiety maintained coordination with metal ions at the active site.
Twelve candidate compounds with the best binding scores were selected
as novel galloyl derivatives with improved RNase H inhibitory activity.