Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring

J Med Chem. 2012 Apr 12;55(7):3387-97. doi: 10.1021/jm300072d. Epub 2012 Mar 22.


GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR(I47V), PR(L76V), PR(V82A), and PR(N88D). Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR(I47V) and PR(L76V) and the altered charge of PR(N88D) are associated with significant local structural changes compared to the wild-type PR(WT), while substitution of alanine in PR(V82A) increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR(WT) with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.

Publication types

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

MeSH terms

  • Carbamates / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Resistance, Viral*
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemistry*
  • HIV-1 / enzymology*
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Pyrrolidinones / chemistry*
  • Sulfonamides / chemistry*


  • Carbamates
  • GRL 02031
  • HIV Protease Inhibitors
  • Pyrrolidinones
  • Sulfonamides
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1

Associated data

  • PDB/3VF5
  • PDB/3VF7
  • PDB/3VFA
  • PDB/3VFB