Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease.
Identifieur interne : 001953 ( Main/Exploration ); précédent : 001952; suivant : 001954Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease.
Auteurs : Jon Jacobs [États-Unis] ; Valerie Grum-Tokars ; Ya Zhou ; Mark Turlington ; S Adrian Saldanha ; Peter Chase ; Aimee Eggler ; Eric S. Dawson ; Yahira M. Baez-Santos ; Sakshi Tomar ; Anna M. Mielech ; Susan C. Baker ; Craig W. Lindsley ; Peter Hodder ; Andrew Mesecar ; Shaun R. StaufferSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2013.
Descripteurs français
- KwdFr :
- Acétamides (), Acétamides (pharmacologie), Acétamides (synthèse chimique), Bibliothèques de petites molécules, Découverte de médicament, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Modèles moléculaires, Relation structure-activité, Spectroscopie par résonance magnétique, Structure moléculaire, Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- pharmacologie : Acétamides, Inhibiteurs de protéases.
- synthèse chimique : Acétamides, Inhibiteurs de protéases.
- virologie : Syndrome respiratoire aigu sévère.
- Acétamides, Bibliothèques de petites molécules, Découverte de médicament, Inhibiteurs de protéases, Modèles moléculaires, Relation structure-activité, Spectroscopie par résonance magnétique, Structure moléculaire.
English descriptors
- KwdEn :
- Acetamides (chemical synthesis), Acetamides (chemistry), Acetamides (pharmacology), Drug Discovery, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), SARS Virus (enzymology), Severe Acute Respiratory Syndrome (virology), Small Molecule Libraries, Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : Acetamides, Protease Inhibitors.
- chemical , chemistry : Acetamides, Protease Inhibitors.
- chemical , pharmacology : Acetamides, Protease Inhibitors.
- enzymology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Drug Discovery, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Small Molecule Libraries, Structure-Activity Relationship.
Abstract
A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.
DOI: 10.1021/jm301580n
PubMed: 23231439
Affiliations:
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Le document en format XML
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Dawson</name></author><author><name sortKey="Baez Santos, Yahira M" sort="Baez Santos, Yahira M" uniqKey="Baez Santos Y" first="Yahira M" last="Baez-Santos">Yahira M. Baez-Santos</name></author><author><name sortKey="Tomar, Sakshi" sort="Tomar, Sakshi" uniqKey="Tomar S" first="Sakshi" last="Tomar">Sakshi Tomar</name></author><author><name sortKey="Mielech, Anna M" sort="Mielech, Anna M" uniqKey="Mielech A" first="Anna M" last="Mielech">Anna M. Mielech</name></author><author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name></author><author><name sortKey="Lindsley, Craig W" sort="Lindsley, Craig W" uniqKey="Lindsley C" first="Craig W" last="Lindsley">Craig W. Lindsley</name></author><author><name sortKey="Hodder, Peter" sort="Hodder, Peter" uniqKey="Hodder P" first="Peter" last="Hodder">Peter Hodder</name></author><author><name sortKey="Mesecar, Andrew" sort="Mesecar, Andrew" uniqKey="Mesecar A" first="Andrew" last="Mesecar">Andrew Mesecar</name></author><author><name sortKey="Stauffer, Shaun R" sort="Stauffer, Shaun R" uniqKey="Stauffer S" first="Shaun R" last="Stauffer">Shaun R. Stauffer</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetamides (chemical synthesis)</term><term>Acetamides (chemistry)</term><term>Acetamides (pharmacology)</term><term>Drug Discovery</term><term>Magnetic Resonance Spectroscopy</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Protease Inhibitors (chemical synthesis)</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (pharmacology)</term><term>SARS Virus (enzymology)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Small Molecule Libraries</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acétamides ()</term><term>Acétamides (pharmacologie)</term><term>Acétamides (synthèse chimique)</term><term>Bibliothèques de petites molécules</term><term>Découverte de médicament</term><term>Inhibiteurs de protéases ()</term><term>Inhibiteurs de protéases (pharmacologie)</term><term>Inhibiteurs de protéases (synthèse chimique)</term><term>Modèles moléculaires</term><term>Relation structure-activité</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Acetamides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acetamides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Acetamides</term><term>Protease Inhibitors</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acétamides</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Acétamides</term><term>Inhibiteurs de protéases</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Drug Discovery</term><term>Magnetic Resonance Spectroscopy</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Small Molecule Libraries</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acétamides</term><term>Bibliothèques de petites molécules</term><term>Découverte de médicament</term><term>Inhibiteurs de protéases</term><term>Modèles moléculaires</term><term>Relation structure-activité</term><term>Spectroscopie par résonance magnétique</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Baez Santos, Yahira M" sort="Baez Santos, Yahira M" uniqKey="Baez Santos Y" first="Yahira M" last="Baez-Santos">Yahira M. Baez-Santos</name><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name><name sortKey="Chase, Peter" sort="Chase, Peter" uniqKey="Chase P" first="Peter" last="Chase">Peter Chase</name><name sortKey="Dawson, Eric S" sort="Dawson, Eric S" uniqKey="Dawson E" first="Eric S" last="Dawson">Eric S. Dawson</name><name sortKey="Eggler, Aimee" sort="Eggler, Aimee" uniqKey="Eggler A" first="Aimee" last="Eggler">Aimee Eggler</name><name sortKey="Grum Tokars, Valerie" sort="Grum Tokars, Valerie" uniqKey="Grum Tokars V" first="Valerie" last="Grum-Tokars">Valerie Grum-Tokars</name><name sortKey="Hodder, Peter" sort="Hodder, Peter" uniqKey="Hodder P" first="Peter" last="Hodder">Peter Hodder</name><name sortKey="Lindsley, Craig W" sort="Lindsley, Craig W" uniqKey="Lindsley C" first="Craig W" last="Lindsley">Craig W. Lindsley</name><name sortKey="Mesecar, Andrew" sort="Mesecar, Andrew" uniqKey="Mesecar A" first="Andrew" last="Mesecar">Andrew Mesecar</name><name sortKey="Mielech, Anna M" sort="Mielech, Anna M" uniqKey="Mielech A" first="Anna M" last="Mielech">Anna M. Mielech</name><name sortKey="Saldanha, S Adrian" sort="Saldanha, S Adrian" uniqKey="Saldanha S" first="S Adrian" last="Saldanha">S Adrian Saldanha</name><name sortKey="Stauffer, Shaun R" sort="Stauffer, Shaun R" uniqKey="Stauffer S" first="Shaun R" last="Stauffer">Shaun R. Stauffer</name><name sortKey="Tomar, Sakshi" sort="Tomar, Sakshi" uniqKey="Tomar S" first="Sakshi" last="Tomar">Sakshi Tomar</name><name sortKey="Turlington, Mark" sort="Turlington, Mark" uniqKey="Turlington M" first="Mark" last="Turlington">Mark Turlington</name><name sortKey="Zhou, Ya" sort="Zhou, Ya" uniqKey="Zhou Y" first="Ya" last="Zhou">Ya Zhou</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Jacobs, Jon" sort="Jacobs, Jon" uniqKey="Jacobs J" first="Jon" last="Jacobs">Jon Jacobs</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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