Constrained search of conformational hyperspace

Richard A. Dammkoehler, Steven F. Karasek, E. F.Berkley Shands, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

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.

Original languageEnglish
Pages (from-to)3-21
Number of pages19
JournalJournal of Computer-Aided Molecular Design
Volume3
Issue number1
DOIs
StatePublished - Mar 1 1989

Keywords

  • Active analog approach
  • Active site geometry
  • Angiotensin converting enzyme
  • Pharmacophore
  • Systematic search

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