Document 0004
 DOCN  M9550004
 TI    Competitive inhibition of HIV-1 protease by biphenyl carboxylic acids.
 DT    9505
 AU    Tummino PJ; Ferguson D; Jacobs CM; Tait B; Hupe L; Lunney E; Hupe D;
       Department of Biochemistry, Parke-Davis Pharmaceutical Research,;
       Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
 SO    Arch Biochem Biophys. 1995 Jan 10;316(1):523-8. Unique Identifier :
       AIDSLINE MED/95142674
 AB    A novel series of nonpeptidic compounds that contain a biphenyl
       carboxylic acid group have been shown to inhibit HIV-1 protease. The
       active compounds, most of which are highly soluble, have IC50 values in
       the range of 3.4-74 microM. The structure-inhibitory activity
       relationship demonstrates the necessity of the biphenyl carboxylic acid
       group for inhibition, which is enhanced by the presence of a sulfone
       group and by halogenation of an adjacent phenyl group. A double
       reciprocal plot of inhibition data on two of the compounds clearly shows
       that the inhibition occurs in a competitive manner, with Ki values of
       1.1 and 3.4 microM. Inhibition by several of the compounds was found to
       be reversible and fast-binding, while one of the biphenyl carboxylic
       acids inhibits in a reversible slow-binding manner. Time-dependent
       inhibition studies were conducted on this compound, and it was
       determined to have the kinetic values of kon = 0.18 microM-1min-1, koff
       = 9.7 x 10(-2)min-1, and Ki = 0.14 microM. Thus, the slow-binding
       inhibitor is the most potent in the series. Molecular modeling has
       provided information on a possible binding mode for two different
       biphenyl carboxylic acid inhibitors of HIV-1 protease.
 DE    Amino Acid Sequence  Binding Sites  Biphenyl
       Compounds/CHEMISTRY/*PHARMACOLOGY  Carboxylic
       Acids/CHEMISTRY/*PHARMACOLOGY  Computer Simulation  Drug Design  HIV
       Protease Inhibitors/CHEMISTRY/CLASSIFICATION/*PHARMACOLOGY
       HIV-1/*ENZYMOLOGY  Kinetics  Models, Molecular  Molecular Sequence Data
       Recombinant Proteins/DRUG EFFECTS  Solubility  JOURNAL ARTICLE

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