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M9490595.TXT
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1994-09-24
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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).