A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies

Dorica Mayer, Christopher B. Naylor, Ioan Motoc, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 Å) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation. Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.

Original languageEnglish
Pages (from-to)3-16
Number of pages14
JournalJournal of Computer-Aided Molecular Design
Volume1
Issue number1
DOIs
StatePublished - Apr 1 1987

Keywords

  • Captopril
  • Metallopeptidase
  • Molecular mechanics
  • Pharmacophore
  • Systematic search

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