Validated ligand mapping of ACE active site

Daniel J. Kuster, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 Å, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

Original languageEnglish
Pages (from-to)609-615
Number of pages7
JournalJournal of Computer-Aided Molecular Design
Issue number8
StatePublished - Aug 2005


  • Active analog
  • Angiotensin-converting enzyme (ACE)
  • Captopril
  • Constrained systematic search
  • Enalapril
  • Lisinopril
  • Ramipril


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