Identification of fragments targeting an alternative pocket on HIV-1 gp41 by NMR screening and similarity searching

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Abstract

The HIV-1 envelope glycoprotein gp41 fusion intermediate is a promising drug target for inhibiting viral entry. However, drug development has been impeded by challenges inherent in mediating the underlying protein–protein interaction. Here we report on the identification of fragments that bind to a C-terminal sub-pocket adjacent to the well-known hydrophobic pocket on the NHR coiled coil. Using a specifically designed assay and ligand-based NMR screening of a fragment library, we identified a thioenylaminopyrazole compound with a dissociation constant of ∼500 μM. Interaction with the C-terminal sub-pocket was confirmed by paramagnetic relaxation enhancement NMR experiments, which also yielded the binding mode. Shape-based similarity searching detected additional phenylpyrazole and phenyltriazole fragments within the library, enriching the hit rate over random screening, and revealing molecular features required for activity. Discovery of the novel scaffolds and binding mechanism suggests avenues for extending the interaction surface and improving the potency of a hydrophobic pocket binding inhibitor.

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Acknowledgements

We gratefully acknowledge the financial support of the National Institutes of Health (GM087998 to M.G.). Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081). We thank OpenEye Inc. Scientific Software for providing an academic license. We thank Professor Marc Anderson for assistance with scripts to run OpenEye software, and in

References and notes (29)

  • F. Naider et al.

    Curr. Opin. Struct. Biol.

    (2009)
  • G. Zhou et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • L.R. Whitby et al.

    Bioorg. Med. Chem. Lett.

    (2012)
  • Y. Wang et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • H. Chong et al.

    J. Biol. Chem.

    (2012)
  • M. Caffrey

    Biochim. Biophys. Acta

    (2001)
  • M. Congreve et al.

    Drug Discovery Today

    (2003)
  • D.M. Eckert et al.

    Annu. Rev. Biochem.

    (2001)
  • L. Cai et al.

    ChemMedChem

    (2010)
  • D.C. Chan et al.

    Proc. Natl. Acad. Sci. U.S.A

    (1998)
  • G. Zhou et al.

    J. Med. Chem.

    (2011)
  • M. Gochin et al.

    Curr. Topics Med. Chem.

    (2011)
  • M. Gochin

    Assay Drug Dev. Technol.

    (2012)
  • M. Gochin et al.

    J. Med. Chem.

    (2009)
  • Cited by (0)

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