Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies

J Med Chem. 2013 Sep 12;56(17):6792-802. doi: 10.1021/jm400768f. Epub 2013 Aug 15.


The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • HIV Protease / drug effects*
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Models, Molecular


  • HIV Protease Inhibitors
  • Ligands
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1