Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor.
Identifieur interne : 005050 ( Main/Exploration ); précédent : 005049; suivant : 005051Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor.
Auteurs : Matthew J. Huentelman [États-Unis] ; Jasenka Zubcevic ; Jose A. Hernández Prada ; Xiaodong Xiao ; Dimiter S. Dimitrov ; Mohan K. Raizada ; David A. OstrovSource :
- Hypertension (Dallas, Tex. : 1979) [ 1524-4563 ] ; 2004.
Descripteurs français
- KwdFr :
- Carboxypeptidases (antagonistes et inhibiteurs), Conception de médicament, Conformation des protéines, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (antagonistes et inhibiteurs), Humains, Hypertension artérielle, Liaison aux protéines, Ligands, Peptidyl-Dipeptidase A, Protéines de l'enveloppe virale (antagonistes et inhibiteurs), Protéines recombinantes, Relation structure-activité, Syndrome respiratoire aigu sévère, Transfection, Virus du SRAS.
- MESH :
- antagonistes et inhibiteurs : Carboxypeptidases, Glycoprotéines membranaires, Protéines de l'enveloppe virale.
- Conception de médicament, Conformation des protéines, Glycoprotéine de spicule des coronavirus, Humains, Hypertension artérielle, Liaison aux protéines, Ligands, Peptidyl-Dipeptidase A, Protéines recombinantes, Relation structure-activité, Syndrome respiratoire aigu sévère, Transfection, Virus du SRAS.
English descriptors
- KwdEn :
- 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).
- MESH :
- chemical , antagonists & inhibitors : Carboxypeptidases, Membrane Glycoproteins, Viral Envelope Proteins.
- Drug Design, Humans, Hypertension, Ligands, Peptidyl-Dipeptidase A, Protein Binding, Protein Conformation, Recombinant Proteins, SARS Virus, Severe Acute Respiratory Syndrome, Spike Glycoprotein, Coronavirus, Structure-Activity Relationship, Transfection.
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.
DOI: 10.1161/01.HYP.0000146120.29648.36
PubMed: 15492138
Affiliations:
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Ostrov</name></author></analytic><series><title level="j">Hypertension (Dallas, Tex. : 1979)</title><idno type="eISSN">1524-4563</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Carboxypeptidases (antagonists & inhibitors)</term><term>Drug Design</term><term>Humans</term><term>Hypertension</term><term>Ligands</term><term>Membrane Glycoproteins (antagonists & inhibitors)</term><term>Peptidyl-Dipeptidase A</term><term>Protein Binding</term><term>Protein Conformation</term><term>Recombinant Proteins</term><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term><term>Spike Glycoprotein, Coronavirus</term><term>Structure-Activity Relationship</term><term>Transfection</term><term>Viral Envelope Proteins (antagonists & inhibitors)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Carboxypeptidases (antagonistes et inhibiteurs)</term><term>Conception de médicament</term><term>Conformation des protéines</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires (antagonistes et inhibiteurs)</term><term>Humains</term><term>Hypertension artérielle</term><term>Liaison aux protéines</term><term>Ligands</term><term>Peptidyl-Dipeptidase A</term><term>Protéines de l'enveloppe virale (antagonistes et inhibiteurs)</term><term>Protéines recombinantes</term><term>Relation structure-activité</term><term>Syndrome respiratoire aigu sévère</term><term>Transfection</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Carboxypeptidases</term><term>Membrane Glycoproteins</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Carboxypeptidases</term><term>Glycoprotéines membranaires</term><term>Protéines de l'enveloppe virale</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Drug Design</term><term>Humans</term><term>Hypertension</term><term>Ligands</term><term>Peptidyl-Dipeptidase A</term><term>Protein Binding</term><term>Protein Conformation</term><term>Recombinant Proteins</term><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term><term>Spike Glycoprotein, Coronavirus</term><term>Structure-Activity Relationship</term><term>Transfection</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conception de médicament</term><term>Conformation des protéines</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Hypertension artérielle</term><term>Liaison aux protéines</term><term>Ligands</term><term>Peptidyl-Dipeptidase A</term><term>Protéines recombinantes</term><term>Relation structure-activité</term><term>Syndrome respiratoire aigu sévère</term><term>Transfection</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Dimitrov, Dimiter S" sort="Dimitrov, Dimiter S" uniqKey="Dimitrov D" first="Dimiter S" last="Dimitrov">Dimiter S. Dimitrov</name><name sortKey="Hernandez Prada, Jose A" sort="Hernandez Prada, Jose A" uniqKey="Hernandez Prada J" first="Jose A" last="Hernández Prada">Jose A. Hernández Prada</name><name sortKey="Ostrov, David A" sort="Ostrov, David A" uniqKey="Ostrov D" first="David A" last="Ostrov">David A. Ostrov</name><name sortKey="Raizada, Mohan K" sort="Raizada, Mohan K" uniqKey="Raizada M" first="Mohan K" last="Raizada">Mohan K. Raizada</name><name sortKey="Xiao, Xiaodong" sort="Xiao, Xiaodong" uniqKey="Xiao X" first="Xiaodong" last="Xiao">Xiaodong Xiao</name><name sortKey="Zubcevic, Jasenka" sort="Zubcevic, Jasenka" uniqKey="Zubcevic J" first="Jasenka" last="Zubcevic">Jasenka Zubcevic</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Huentelman, Matthew J" sort="Huentelman, Matthew J" uniqKey="Huentelman M" first="Matthew J" last="Huentelman">Matthew J. Huentelman</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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