Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure

J Med Chem. 2011 Aug 25;54(16):5890-901. doi: 10.1021/jm200649p. Epub 2011 Jul 29.

Abstract

We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Biocatalysis / drug effects
  • Cell Line
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Protease / chemistry
  • HIV Protease / genetics
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Humans
  • Ligands*
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Urethane / chemistry
  • Urethane / metabolism*
  • Urethane / pharmacology

Substances

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

Associated data

  • PDB/3ST5