Document 0595
 DOCN  M9490595
 TI    A novel nonpeptide HIV-1 protease inhibitor: elucidation of the binding
       mode and its application in the design of related analogs.
 DT    9411
 AU    Lunney EA; Hagen SE; Domagala JM; Humblet C; Kosinski J; Tait BD; Warmus
       JS; Wilson M; Ferguson D; Hupe D; et al; Parke-Davis Pharmaceutical
       Research, Division of Warner Lambert,; Ann Arbor, Michigan 48105-2430.
 SO    J Med Chem. 1994 Aug 19;37(17):2664-77. Unique Identifier : AIDSLINE
       MED/94343455
 AB    HIV-1 protease has been identified as a significant target enzyme in
       AIDS research. While numerous peptide-derived inhibitors have been
       described, the identification of a nonpeptide inhibitor remains an
       important goal. Using an HIV-1 protease mass screening technique,
       4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified
       as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte
       Carlo-based docking procedure, the coumarin was docked in the active
       site of the enzyme, revealing a binding mode that was later confirmed by
       the X-ray crystal analysis. Several analogs were prepared to test the
       binding interactions and improve the overall binding affinity. The most
       active compound in the study was
       4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).
 DE    Acquired Immunodeficiency Syndrome/DRUG THERAPY  Binding Sites
       Comparative Study  Coumarins/*CHEMISTRY/CHEMICAL SYNTHESIS/METABOLISM
       Crystallography, X-Ray  Drug Design  Human  HIV
       Protease/*CHEMISTRY/METABOLISM  HIV Protease
       Inhibitors/*CHEMISTRY/METABOLISM  HIV-1/ENZYMOLOGY  Models, Molecular
       Molecular Conformation  Molecular Structure  Monte Carlo Method
       Oligopeptides/CHEMISTRY/METABOLISM  Protein Conformation
       4-Hydroxycoumarins/*CHEMISTRY/METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).