Identification of alternative binding sites for inhibitors of HIV-1 ribonuclease H through comparative analysis of virtual enrichment studies

J Chem Inf Model. 2011 Aug 22;51(8):1986-98. doi: 10.1021/ci200194w. Epub 2011 Jul 26.


The ribonuclease H (RNase H) domain on the p66 monomer of HIV-1 reverse transcriptase enzyme has become a target for inhibition. The active site is one potential binding site, but other RNase H sites can accommodate inhibitors. Using a combination of experimental and computational studies, potential new binding sites and binding modes have been identified. Libraries of compounds were screened with an experimental assay to identify actives without knowledge of the binding site. The compounds were computationally docked at putative binding sites. Based on positive enrichment of natural-product actives relative to the database of compounds, we propose that many inhibitors bind to an alternative, potentially allosteric, site centered on Q507 of p66. For a series of hydrazone compounds, a small amount of positive enrichment was obtained when active compounds were bound by induced-fit docking at the interface between the DNA:RNA substrate and the RNase H domain near residue Q500.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Site / drug effects
  • Binding Sites
  • Catalytic Domain / drug effects
  • Computer Simulation
  • Glutamine / chemistry
  • Glutamine / genetics
  • Glutamine / metabolism*
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Reverse Transcriptase / analysis
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1* / chemistry
  • HIV-1* / enzymology
  • Humans
  • Hydrazines / chemistry
  • Hydrazines / metabolism*
  • Hydrazines / pharmacology
  • Hydrazones / chemistry
  • Hydrazones / metabolism*
  • Hydrazones / pharmacology
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • ROC Curve
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / metabolism*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonuclease H / analysis
  • Ribonuclease H / chemistry
  • Ribonuclease H / metabolism*
  • Small Molecule Libraries


  • Hydrazines
  • Hydrazones
  • Reverse Transcriptase Inhibitors
  • Small Molecule Libraries
  • Glutamine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • Ribonuclease H