Published Online
on October 18, 2004

A more recent version of this article appeared on December 1, 2004

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Submitted on July 23, 2004
Revised on August 19, 2004

Structure-Based Discovery of a Novel Angiotensin-Converting Enzyme 2 Inhibitor

Matthew J. Huentelman; Jasenka Zubcevic; Jose A. Hernández Prada; Xiaodong Xiao; Dimiter S. Dimitrov; Mohan K. Raizada^*; and David A. Ostrov

From the Department of Physiology and Functional Genomics (M.J.H., J.Z., M.K.R.) and Pathology and Department of Immunology and Laboratory Medicine (J.A.H.P., D.A.O.), College of Medicine, University of Florida, Gainesville, Fla; McKnight Brain Institute (M.J.H., J.Z., M.K.R.), Gainesville, Fla; and Laboratory of Experimental and Computational Biology (X.X., D.S.D.), CCR, National Cancer Institute Frederick, National Institutes of Health, Frederick, Md.

^* To whom correspondence should be addressed. E-mail: mraizada{at}phys.med.ufl.edu.

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, 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.

Key words: angiotensin-converting enzyme • cardiovascular diseases • hypertension

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