Mechanism-based analysis of enzyme inhibitors of amide bond hydrolysis.
Biochemical information regarding the mechanism of amide bond hydrolysis offers insight into the possible chemical groups in the enzyme active site responsible for hydrolysis. Assuming that these groups have a relatively fixed geometry in accord with their functional role, then their three-dimensional position in space can be determined if sufficient structural diversity exists within the data set of compounds with known affinities. Each compound which binds can be augmented by additional chemical groups to represent the receptor's functional groups. For each compound, the set of geometrical arrangements of these groups which would show optimal binding to the compound can be determined by systematic search. A common geometric arrangement representing the active site geometry should be present for each compound. In studies of the binding of mechanism-based inhibitors of chymotrypsin, Naruto et al. (1985) showed some movement of active site residues to accommodate different ligands. Nevertheless, this procedure found a unique active site geometry for ACE which compared favorably with that of carboxypeptidase A, an enzyme of analogous function.
Marshall
G R
GR
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Mayer
D
D
Naylor
C B
CB
Hodgkin
E E
EE
Cramer
R D
RD
D000577:Amides; D001665:Binding Sites; D002800:Cholinesterase Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors; D006868:Hydrolysis; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000577:Amides; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors