HIV-1 protease inhibitors: ketomethylene isosteres with unusually high affinity compared with hydroxyethylene isostere analogs.
HIV protease is a member of the aspartic proteinase family of proteolytic enzymes which include pepsin and renin. In contrast to the enhanced affinity seen with renin and pepsin upon conversion of the transition-state isostere, ketomethylene, to the hydroxyethylene, a set of HIV protease inhibitors showed a reduction in affinity. This implies that interactions with the active site of other segments of the inhibitor than those of the transition-state analog must predominate in the case of HIV protease, and that observations made on mammalian aspartic proteinases do not necessarily apply to viral aspartic proteinases.
Marinier
A
A
Department of Moelcular Biology and Pharmacology, Washington University, St. Louis, MO 63130.
Toth
M V
MV
Houseman
K
K
Mueller
R
R
Marshall
G R
GR
D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D001665:Binding Sites; D005030:Ethylenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D007536:Isomerism; D007659:Ketones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D005030:Ethylenes; D017320:HIV Protease Inhibitors; D007659:Ketones; D009842:Oligopeptides; C036216:ethylene