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

Abstract

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.

• Authors: Matthew J Huentelman, Jasenka Zubcevic, Jose A Hernández Prada, Xiaodong Xiao, Dimiter S Dimitrov, Mohan K Raizada, David A Ostrov
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 44 Issue 6 Pg. 903-6 (Dec 2004) ISSN: 1524-4563 [Electronic] United States
• PMID: 15492138 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• 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
• Severe acute respiratory syndrome-related coronavirus
• Severe Acute Respiratory Syndrome
• Spike Glycoprotein, Coronavirus
• Structure-Activity Relationship
• Transfection
• Viral Envelope Proteins (antagonists & inhibitors)