Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor

Hypertension. 2004 Dec;44(6):903-6. doi: 10.1161/01.HYP.0000146120.29648.36. Epub 2004 Oct 18.


Angiotensin-converting enzyme 2 (ACE2) is considered an important therapeutic target for controlling cardiovascular diseases and severe acute respiratory syndrome (SARS) outbreaks. Recently solved high-resolution crystal structures of the apo-bound and inhibitor-bound forms of ACE2 have provided the basis for a novel molecular docking approach in an attempt to identify ACE2 inhibitors and compounds that block SARS coronavirus spike protein-mediated cell fusion. In this study, approximately 140 000 small molecules were screened by in silico molecular docking. In this structure-activity relation study, the molecules with the highest predicted binding scores were identified and assayed for ACE2 enzymatic inhibitory activity and for their ability to inhibit SARS coronavirus spike protein-mediated cell fusion. This approach identified N-(2-aminoethyl)-1 aziridine-ethanamine as a novel ACE2 inhibitor that also is effective in blocking the SARS coronavirus spike protein-mediated cell fusion. Thus, the molecular docking approach resulting in the inhibitory capacity of N-(2-aminoethyl)-1 aziridine-ethanamine provides an attractive small molecule lead compound on which the development of more effective therapeutic agents could be developed to modulate hypertension and for controlling SARS infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Carboxypeptidases / antagonists & inhibitors*
  • Drug Design*
  • Humans
  • Hypertension
  • Ligands
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Peptidyl-Dipeptidase A
  • Protein Binding
  • Protein Conformation
  • Recombinant Proteins
  • SARS Virus
  • Severe Acute Respiratory Syndrome
  • Spike Glycoprotein, Coronavirus
  • Structure-Activity Relationship*
  • Transfection
  • Viral Envelope Proteins / antagonists & inhibitors*


  • Ligands
  • Membrane Glycoproteins
  • Recombinant Proteins
  • Spike Glycoprotein, Coronavirus
  • Viral Envelope Proteins
  • spike glycoprotein, SARS-CoV
  • Carboxypeptidases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2