Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs

Daniel M. Himmel, Nataliya S. Myshakina, Tatiana Ilina, Alexander Van Ry, William C. Ho, Michael A. Parniak, Eddy Arnold

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Human immunodeficiency virus (HIV) encodes four essential enzymes: protease, integrase, reverse transcriptase (RT)-associated DNA polymerase, and RT-associated ribonuclease H (RNase H). Current clinically approved anti-AIDS drugs target all HIV enzymatic activities except RNase H, which has proven to be a very difficult target for HIV drug discovery. Our high-throughput screening activities identified the dihydroxycoumarin compound F3284-8495 as a specific inhibitor of RT RNase H, with low micromolar potency in vitro. Optimization of inhibitory potency can be facilitated by structural information about inhibitor-target binding. Here, we report the crystal structure of F3284-8495 bound to the active site of an isolated RNase H domain of HIV-1 RT at a resolution limit of 1.71 Å. From predictions based on this structure, compounds were obtained that showed improved inhibitory activity. Computational analysis suggested structural alterations that could provide additional interactions with RT and thus improve inhibitory potency. These studies established proof of concept that F3284-8495 could be used as a favorable chemical scaffold for development of HIV RNase H inhibitors.

Original languageEnglish (US)
Pages (from-to)2617-2631
Number of pages15
JournalJournal of molecular biology
Volume426
Issue number14
DOIs
StatePublished - Jul 15 2014

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Keywords

  • HIV ribonuclease H
  • RNase H inhibitors
  • dihydroxybenzopyrone derivatives
  • protein-inhibitor complex
  • structure-based drug design

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