title: 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.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Fla 32610, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Jose A
authors.initials: JA
authors.lastname: Hernández Prada
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xiao
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D006973:Hypertension; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins; D045473:Severe acute respiratory syndrome-related coronavirus; D045169:Severe Acute Respiratory Syndrome; D064370:Spike Glycoprotein, Coronavirus; D013329:Structure-Activity Relationship; D014162:Transfection; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors*
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2