Constrained search of conformational hyperspace.
We introduce a new method for determining pharmacophore or active site geometries by analysis of the structures of a series of active compounds. The method, constrained search, and the key concepts on which it is based, is described and illustrated by its application to 28 potent inhibitors of angiotensin-converting enzyme (ACE). The data set is one utilized by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3-16] to determine a unique geometry for the active site. Our experiment validated the previously reported results, obtained by a systematic search, while reducing the computer time requirement by more than two orders of magnitude. The experiment also identified a previously unrecognized alternative active site geometry for the ACE series.
Dammkoehler
R A
RA
Department of Computer Science, Washington University, St. Louis, MO 63130.
Karasek
S F
SF
Shands
E F
EF
Marshall
G R
GR
D000806:Angiotensin-Converting Enzyme Inhibitors; D001665:Binding Sites; D003198:Computer Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors