Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.
Identifieur interne : 000C31 ( Main/Exploration ); précédent : 000C30; suivant : 000C32Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.
Auteurs : Cy V. Credille [États-Unis] ; Benjamin L. Dick [États-Unis] ; Christine N. Morrison [États-Unis] ; Ryjul W. Stokes [États-Unis] ; Rebecca N. Adamek [États-Unis] ; Nicholas C. Wu [États-Unis] ; Ian A. Wilson [États-Unis] ; Seth M. Cohen [États-Unis]Source :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2018.
Descripteurs français
- KwdFr :
- Antienzymes (), Antienzymes (métabolisme), Antienzymes (pharmacologie), Concentration inhibitrice 50, Conformation des protéines, DNA-directed RNA polymerases (), DNA-directed RNA polymerases (antagonistes et inhibiteurs), DNA-directed RNA polymerases (métabolisme), Découverte de médicament, Endonucleases (), Endonucleases (antagonistes et inhibiteurs), Endonucleases (métabolisme), Humains, Modèles moléculaires, Métaux (métabolisme), Relation structure-activité, Sous-type H1N1 du virus de la grippe A (enzymologie).
- MESH :
- antagonistes et inhibiteurs : DNA-directed RNA polymerases, Endonucleases.
- enzymologie : Sous-type H1N1 du virus de la grippe A.
- métabolisme : Antienzymes, DNA-directed RNA polymerases, Endonucleases, Métaux.
- pharmacologie : Antienzymes.
- Antienzymes, Concentration inhibitrice 50, Conformation des protéines, DNA-directed RNA polymerases, Découverte de médicament, Endonucleases, Humains, Modèles moléculaires, Relation structure-activité.
English descriptors
- KwdEn :
- DNA-Directed RNA Polymerases (antagonists & inhibitors), DNA-Directed RNA Polymerases (chemistry), DNA-Directed RNA Polymerases (metabolism), Drug Discovery, Endonucleases (antagonists & inhibitors), Endonucleases (chemistry), Endonucleases (metabolism), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (metabolism), Enzyme Inhibitors (pharmacology), Humans, Influenza A Virus, H1N1 Subtype (enzymology), Inhibitory Concentration 50, Metals (metabolism), Models, Molecular, Protein Conformation, Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : DNA-Directed RNA Polymerases, Endonucleases.
- chemical , chemistry : DNA-Directed RNA Polymerases, Endonucleases, Enzyme Inhibitors.
- chemical , metabolism : DNA-Directed RNA Polymerases, Endonucleases, Enzyme Inhibitors, Metals.
- chemical , pharmacology : Enzyme Inhibitors.
- enzymology : Influenza A Virus, H1N1 Subtype.
- Drug Discovery, Humans, Inhibitory Concentration 50, Models, Molecular, Protein Conformation, Structure-Activity Relationship.
Abstract
Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values <50 nM. This SAR led to structurally distinct molecules that also displayed IC50 values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.
DOI: 10.1021/acs.jmedchem.8b01363
PubMed: 30351002
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000963
- to stream PubMed, to step Curation: 000963
- to stream PubMed, to step Checkpoint: 000959
- to stream Ncbi, to step Merge: 002F81
- to stream Ncbi, to step Curation: 002F81
- to stream Ncbi, to step Checkpoint: 002F81
- to stream Main, to step Merge: 000C33
- to stream Main, to step Curation: 000C31
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.</title><author><name sortKey="Credille, Cy V" sort="Credille, Cy V" uniqKey="Credille C" first="Cy V" last="Credille">Cy V. Credille</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Dick, Benjamin L" sort="Dick, Benjamin L" uniqKey="Dick B" first="Benjamin L" last="Dick">Benjamin L. Dick</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Morrison, Christine N" sort="Morrison, Christine N" uniqKey="Morrison C" first="Christine N" last="Morrison">Christine N. Morrison</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Stokes, Ryjul W" sort="Stokes, Ryjul W" uniqKey="Stokes R" first="Ryjul W" last="Stokes">Ryjul W. Stokes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Adamek, Rebecca N" sort="Adamek, Rebecca N" uniqKey="Adamek R" first="Rebecca N" last="Adamek">Rebecca N. Adamek</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C" last="Wu">Nicholas C. Wu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 </wicri:regionArea><wicri:noRegion>California 92037 </wicri:noRegion></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 </wicri:regionArea><wicri:noRegion>California 92037 </wicri:noRegion></affiliation></author><author><name sortKey="Cohen, Seth M" sort="Cohen, Seth M" uniqKey="Cohen S" first="Seth M" last="Cohen">Seth M. Cohen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30351002</idno><idno type="pmid">30351002</idno><idno type="doi">10.1021/acs.jmedchem.8b01363</idno><idno type="wicri:Area/PubMed/Corpus">000963</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000963</idno><idno type="wicri:Area/PubMed/Curation">000963</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000963</idno><idno type="wicri:Area/PubMed/Checkpoint">000959</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000959</idno><idno type="wicri:Area/Ncbi/Merge">002F81</idno><idno type="wicri:Area/Ncbi/Curation">002F81</idno><idno type="wicri:Area/Ncbi/Checkpoint">002F81</idno><idno type="wicri:Area/Main/Merge">000C33</idno><idno type="wicri:Area/Main/Curation">000C31</idno><idno type="wicri:Area/Main/Exploration">000C31</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.</title><author><name sortKey="Credille, Cy V" sort="Credille, Cy V" uniqKey="Credille C" first="Cy V" last="Credille">Cy V. Credille</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Dick, Benjamin L" sort="Dick, Benjamin L" uniqKey="Dick B" first="Benjamin L" last="Dick">Benjamin L. Dick</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Morrison, Christine N" sort="Morrison, Christine N" uniqKey="Morrison C" first="Christine N" last="Morrison">Christine N. Morrison</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Stokes, Ryjul W" sort="Stokes, Ryjul W" uniqKey="Stokes R" first="Ryjul W" last="Stokes">Ryjul W. Stokes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Adamek, Rebecca N" sort="Adamek, Rebecca N" uniqKey="Adamek R" first="Rebecca N" last="Adamek">Rebecca N. Adamek</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author><author><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C" last="Wu">Nicholas C. Wu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 </wicri:regionArea><wicri:noRegion>California 92037 </wicri:noRegion></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 </wicri:regionArea><wicri:noRegion>California 92037 </wicri:noRegion></affiliation></author><author><name sortKey="Cohen, Seth M" sort="Cohen, Seth M" uniqKey="Cohen S" first="Seth M" last="Cohen">Seth M. Cohen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 </wicri:regionArea><wicri:noRegion>California 92093 </wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>DNA-Directed RNA Polymerases (antagonists & inhibitors)</term><term>DNA-Directed RNA Polymerases (chemistry)</term><term>DNA-Directed RNA Polymerases (metabolism)</term><term>Drug Discovery</term><term>Endonucleases (antagonists & inhibitors)</term><term>Endonucleases (chemistry)</term><term>Endonucleases (metabolism)</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (metabolism)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Humans</term><term>Influenza A Virus, H1N1 Subtype (enzymology)</term><term>Inhibitory Concentration 50</term><term>Metals (metabolism)</term><term>Models, Molecular</term><term>Protein Conformation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes ()</term><term>Antienzymes (métabolisme)</term><term>Antienzymes (pharmacologie)</term><term>Concentration inhibitrice 50</term><term>Conformation des protéines</term><term>DNA-directed RNA polymerases ()</term><term>DNA-directed RNA polymerases (antagonistes et inhibiteurs)</term><term>DNA-directed RNA polymerases (métabolisme)</term><term>Découverte de médicament</term><term>Endonucleases ()</term><term>Endonucleases (antagonistes et inhibiteurs)</term><term>Endonucleases (métabolisme)</term><term>Humains</term><term>Modèles moléculaires</term><term>Métaux (métabolisme)</term><term>Relation structure-activité</term><term>Sous-type H1N1 du virus de la grippe A (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>DNA-Directed RNA Polymerases</term><term>Endonucleases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA-Directed RNA Polymerases</term><term>Endonucleases</term><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>DNA-Directed RNA Polymerases</term><term>Endonucleases</term><term>Enzyme Inhibitors</term><term>Metals</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>DNA-directed RNA polymerases</term><term>Endonucleases</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Sous-type H1N1 du virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Influenza A Virus, H1N1 Subtype</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antienzymes</term><term>DNA-directed RNA polymerases</term><term>Endonucleases</term><term>Métaux</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Drug Discovery</term><term>Humans</term><term>Inhibitory Concentration 50</term><term>Models, Molecular</term><term>Protein Conformation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antienzymes</term><term>Concentration inhibitrice 50</term><term>Conformation des protéines</term><term>DNA-directed RNA polymerases</term><term>Découverte de médicament</term><term>Endonucleases</term><term>Humains</term><term>Modèles moléculaires</term><term>Relation structure-activité</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA<sub>N</sub> endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PA<sub>N</sub> endonuclease, a class of highly active and selective fragments was developed that displays IC<sub>50</sub> values <50 nM. This SAR led to structurally distinct molecules that also displayed IC<sub>50</sub> values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Credille, Cy V" sort="Credille, Cy V" uniqKey="Credille C" first="Cy V" last="Credille">Cy V. Credille</name></noRegion><name sortKey="Adamek, Rebecca N" sort="Adamek, Rebecca N" uniqKey="Adamek R" first="Rebecca N" last="Adamek">Rebecca N. Adamek</name><name sortKey="Cohen, Seth M" sort="Cohen, Seth M" uniqKey="Cohen S" first="Seth M" last="Cohen">Seth M. Cohen</name><name sortKey="Dick, Benjamin L" sort="Dick, Benjamin L" uniqKey="Dick B" first="Benjamin L" last="Dick">Benjamin L. Dick</name><name sortKey="Morrison, Christine N" sort="Morrison, Christine N" uniqKey="Morrison C" first="Christine N" last="Morrison">Christine N. Morrison</name><name sortKey="Stokes, Ryjul W" sort="Stokes, Ryjul W" uniqKey="Stokes R" first="Ryjul W" last="Stokes">Ryjul W. Stokes</name><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C" last="Wu">Nicholas C. Wu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000C31 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000C31 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:30351002
|texte= Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:30351002" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |