title: Constrained search of conformational hyperspace.
abstract: 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.
authors.affiliation: Department of Computer Science, Washington University, St. Louis, MO 63130.
authors.forename: R A
authors.initials: RA
authors.lastname: Dammkoehler
authors.forename: S F
authors.initials: SF
authors.lastname: Karasek
authors.forename: E F
authors.initials: EF
authors.lastname: Shands
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors; D001665:Binding Sites; D003198:Computer Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors