The discovery, characterization and crystallographically determined binding mode of an FMOC-containing inhibitor of HIV-1 protease

Bioorg Med Chem. 1997 Jul;5(7):1311-20. doi: 10.1016/s0968-0896(97)00078-3.


A pharmacophore derived from the structure of the dithiolane derivative of haloperidol bound in the active site of the HIV-1 protease (HIV-1 PR) has been used to search a three-dimensional database for new inhibitory frameworks. This search identified an FMOC-protected N-tosyl arginine as a lead candidate. A derivative in which the arginine carboxyl has been converted to an amide has been crystallized with HIV-1 PR and the structure has been determined to a resolution of 2.5 A with a final R-factor of 18.5%. The inhibitor binds in an extended conformation that results in occupancy of the S2, S1', and S3' subsites of the active site. Initial structure-activity studies indicate that: (1) the FMOC fluorenyl moiety interacts closely with active site residues and is important for binding; (2) the N(G)-tosyl group is necessary to suppress protonation of the arginine guanidinyl terminus; and (3) the arginine carboxamide function is involved in interactions with the water coordinated to the catalytic aspartyl groups. FMOC-protected arginine derivatives, which appear to be relatively specific and nontoxic, offer promise for the development of useful HIV-1 protease inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / metabolism*
  • Amino Acids / pharmacology
  • Arginine / analogs & derivatives*
  • Arginine / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • Fluorenes / chemistry*
  • Fluorenes / metabolism*
  • Fluorenes / pharmacology
  • HIV Protease / chemistry*
  • HIV Protease / drug effects
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology
  • Haloperidol / analogs & derivatives
  • Protein Conformation
  • Structure-Activity Relationship


  • Amino Acids
  • Fluorenes
  • HIV Protease Inhibitors
  • N(alpha)-FMOC-N(omega)-tosylarginine
  • N(alpha)-fluorenylmethyloxycarbonylamino acids
  • Arginine
  • HIV Protease
  • Haloperidol