Document 0811
 DOCN  M9550811
 TI    Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside
       inhibitors.
 DT    9505
 AU    Spence RA; Kati WM; Anderson KS; Johnson KA; Department of Biochemistry
       and Molecular Biology, Pennsylvania; State University, University Park
       16802.
 SO    Science. 1995 Feb 17;267(5200):988-93. Unique Identifier : AIDSLINE
       MED/95167499
 AB    The mechanism of inhibition of HIV-1 reverse transcriptase by three
       nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO
       each bind to a hydrophobic pocket in the enzyme-DNA complex close to the
       active site catalytic residues. Pre-steady-state kinetic analysis was
       used to establish the mechanism of inhibition by these noncompetitive
       inhibitors. Analysis of the pre-steady-state burst of DNA polymerization
       indicated that inhibitors blocked the chemical reaction, but did not
       interfere with nucleotide binding or the nucleotide-induced
       conformational change. Rather, in the presence of saturating
       concentrations of the inhibitors, the nucleoside triphosphate bound
       tightly (Kd, 100 nM), but nonproductively. The data suggest that an
       inhibitor combining the functionalities of a nonnucleoside inhibitor and
       a nucleotide analog could bind very tightly and specifically to reverse
       transcriptase and could be effective in the treatment of AIDS.
 DE    Antiviral Agents/METABOLISM/*PHARMACOLOGY
       Benzodiazepines/METABOLISM/*PHARMACOLOGY  Binding Sites  Deoxyadenine
       Nucleotides/METABOLISM  DNA/METABOLISM  HIV-1/DRUG EFFECTS/*ENZYMOLOGY
       Imidazoles/METABOLISM/*PHARMACOLOGY  Kinetics
       Magnesium/METABOLISM/PHARMACOLOGY  Protein Conformation
       Pyridines/METABOLISM/*PHARMACOLOGY  Reverse Transcriptase/*ANTAGONISTS &
       INHIB/CHEMISTRY/METABOLISM  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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