Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere

J Med Chem. 1994 Sep 16;37(19):3100-7. doi: 10.1021/jm00045a015.


The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.

Publication types

  • Comparative Study

MeSH terms

  • Amides / chemical synthesis*
  • Amides / metabolism
  • Amides / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • HIV Protease / drug effects
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / pharmacology*
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Reproducibility of Results
  • Stereoisomerism
  • Structure-Activity Relationship
  • Valine / analogs & derivatives
  • Valine / chemical synthesis
  • Valine / chemistry
  • Valine / pharmacology


  • Amides
  • HIV Protease Inhibitors
  • Imidazoles
  • SB 206343
  • HIV Protease
  • Valine