Design and synthesis of unsymmetrical peptidyl urea inhibitors of aspartic peptidases.
[structure: see text] The design, synthesis, and enzyme inhibition of a new class of aspartic peptidase inhibitors is described. Unsymmetrical ureas were designed from computer-generated structures. Using mechanism-based and substrate-based design techniques, potent pepsin inhibitors were developed and the binding mode was established. Two X-ray crystal structures of enzyme-bound inhibitors revealed a new binding mode that is closely related to the computer-generated binding mode.
Dales
N A
NA
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA.
Bohacek
R S
RS
Satyshur
K A
KA
Rich
D H
DH
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D010434:Pepsin A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D010455:Peptides; D011480:Protease Inhibitors; D014508:Urea; D016282:Aspartic Acid Endopeptidases; D010434:Pepsin A; C035794:rhizopuspepsin