GlutaredoxinV1, Main, Exploration, bibRecord, 000154

Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.

Identifieur interne : 000154 ( Main/Exploration ); précédent : 000153; suivant : 000155

Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.

Auteurs : Ram B. Khattri [États-Unis] ; Daniel L. Morris [États-Unis] ; Stephanie M. Bilinovich [États-Unis] ; Erendra Manandhar [États-Unis] ; Kahlilah R. Napper [États-Unis] ; Jacob W. Sweet [États-Unis] ; David A. Modarelli [États-Unis] ; Thomas C. Leeper [États-Unis]

Source :

Molecules (Basel, Switzerland) [ 1420-3049 ] ; 2019.

RBID : pubmed:31905878

Descripteurs français

KwdFr :
- Acrylamide (composition chimique), Antibactériens (composition chimique), Antibactériens (pharmacologie), Antibactériens (synthèse chimique), Bibliothèques de petites molécules (composition chimique), Bibliothèques de petites molécules (pharmacologie), Bibliothèques de petites molécules (synthèse chimique), Cinétique (MeSH), Glutarédoxines (antagonistes et inhibiteurs), Glutarédoxines (composition chimique), Humains (MeSH), Modèles moléculaires (MeSH), Plomb (composition chimique), Protéines bactériennes (antagonistes et inhibiteurs), Protéines bactériennes (composition chimique), Pseudomonas aeruginosa (effets des médicaments et des substances chimiques), Pseudomonas aeruginosa (enzymologie), Relation structure-activité (MeSH), Résonance magnétique nucléaire biomoléculaire (MeSH), Simulation de docking moléculaire (MeSH), Spécificité d'espèce (MeSH), Structure moléculaire (MeSH).
MESH :
- antagonistes et inhibiteurs : Glutarédoxines, Protéines bactériennes.
- composition chimique : Acrylamide, Antibactériens, Bibliothèques de petites molécules, Glutarédoxines, Plomb, Protéines bactériennes.
- effets des médicaments et des substances chimiques : Pseudomonas aeruginosa.
- enzymologie : Pseudomonas aeruginosa.
- pharmacologie : Antibactériens, Bibliothèques de petites molécules.
- synthèse chimique : Antibactériens, Bibliothèques de petites molécules.
- Cinétique, Humains, Modèles moléculaires, Relation structure-activité, Résonance magnétique nucléaire biomoléculaire, Simulation de docking moléculaire, Spécificité d'espèce, Structure moléculaire.

English descriptors

KwdEn :
- Acrylamide (chemistry), Anti-Bacterial Agents (chemical synthesis), Anti-Bacterial Agents (chemistry), Anti-Bacterial Agents (pharmacology), Bacterial Proteins (antagonists & inhibitors), Bacterial Proteins (chemistry), Glutaredoxins (antagonists & inhibitors), Glutaredoxins (chemistry), Humans (MeSH), Kinetics (MeSH), Lead (chemistry), Models, Molecular (MeSH), Molecular Docking Simulation (MeSH), Molecular Structure (MeSH), Nuclear Magnetic Resonance, Biomolecular (MeSH), Pseudomonas aeruginosa (drug effects), Pseudomonas aeruginosa (enzymology), Small Molecule Libraries (chemical synthesis), Small Molecule Libraries (chemistry), Small Molecule Libraries (pharmacology), Species Specificity (MeSH), Structure-Activity Relationship (MeSH).
MESH :
- chemical , antagonists & inhibitors : Bacterial Proteins, Glutaredoxins.
- chemical , chemical synthesis : Anti-Bacterial Agents, Small Molecule Libraries.
- chemical , chemistry : Acrylamide, Anti-Bacterial Agents, Bacterial Proteins, Glutaredoxins, Lead, Small Molecule Libraries.
- chemical , pharmacology : Anti-Bacterial Agents, Small Molecule Libraries.
- drug effects : Pseudomonas aeruginosa.
- enzymology : Pseudomonas aeruginosa.
- Humans, Kinetics, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Species Specificity, Structure-Activity Relationship.

Abstract

Illustrated here is the development of a new class of antibiotic lead molecules targeted at Pseudomonas aeruginosa glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable.

DOI: 10.3390/molecules25010147
PubMed: 31905878
PubMed Central: PMC6983068

Affiliations:

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000090
to stream Main, to step Curation: 000090

Le document en format XML

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<term>Anti-Bacterial Agents (chemical synthesis)</term>
<term>Anti-Bacterial Agents (chemistry)</term>
<term>Anti-Bacterial Agents (pharmacology)</term>
<term>Bacterial Proteins (antagonists & inhibitors)</term>
<term>Bacterial Proteins (chemistry)</term>
<term>Glutaredoxins (antagonists & inhibitors)</term>
<term>Glutaredoxins (chemistry)</term>
<term>Humans (MeSH)</term>
<term>Kinetics (MeSH)</term>
<term>Lead (chemistry)</term>
<term>Models, Molecular (MeSH)</term>
<term>Molecular Docking Simulation (MeSH)</term>
<term>Molecular Structure (MeSH)</term>
<term>Nuclear Magnetic Resonance, Biomolecular (MeSH)</term>
<term>Pseudomonas aeruginosa (drug effects)</term>
<term>Pseudomonas aeruginosa (enzymology)</term>
<term>Small Molecule Libraries (chemical synthesis)</term>
<term>Small Molecule Libraries (chemistry)</term>
<term>Small Molecule Libraries (pharmacology)</term>
<term>Species Specificity (MeSH)</term>
<term>Structure-Activity Relationship (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Acrylamide (composition chimique)</term>
<term>Antibactériens (composition chimique)</term>
<term>Antibactériens (pharmacologie)</term>
<term>Antibactériens (synthèse chimique)</term>
<term>Bibliothèques de petites molécules (composition chimique)</term>
<term>Bibliothèques de petites molécules (pharmacologie)</term>
<term>Bibliothèques de petites molécules (synthèse chimique)</term>
<term>Cinétique (MeSH)</term>
<term>Glutarédoxines (antagonistes et inhibiteurs)</term>
<term>Glutarédoxines (composition chimique)</term>
<term>Humains (MeSH)</term>
<term>Modèles moléculaires (MeSH)</term>
<term>Plomb (composition chimique)</term>
<term>Protéines bactériennes (antagonistes et inhibiteurs)</term>
<term>Protéines bactériennes (composition chimique)</term>
<term>Pseudomonas aeruginosa (effets des médicaments et des substances chimiques)</term>
<term>Pseudomonas aeruginosa (enzymologie)</term>
<term>Relation structure-activité (MeSH)</term>
<term>Résonance magnétique nucléaire biomoléculaire (MeSH)</term>
<term>Simulation de docking moléculaire (MeSH)</term>
<term>Spécificité d'espèce (MeSH)</term>
<term>Structure moléculaire (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Bacterial Proteins</term>
<term>Glutaredoxins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-Bacterial Agents</term>
<term>Small Molecule Libraries</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acrylamide</term>
<term>Anti-Bacterial Agents</term>
<term>Bacterial Proteins</term>
<term>Glutaredoxins</term>
<term>Lead</term>
<term>Small Molecule Libraries</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Bacterial Agents</term>
<term>Small Molecule Libraries</term>
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<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glutarédoxines</term>
<term>Protéines bactériennes</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Acrylamide</term>
<term>Antibactériens</term>
<term>Bibliothèques de petites molécules</term>
<term>Glutarédoxines</term>
<term>Plomb</term>
<term>Protéines bactériennes</term>
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<term>Bibliothèques de petites molécules</term>
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<term>Bibliothèques de petites molécules</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Humans</term>
<term>Kinetics</term>
<term>Models, Molecular</term>
<term>Molecular Docking Simulation</term>
<term>Molecular Structure</term>
<term>Nuclear Magnetic Resonance, Biomolecular</term>
<term>Species Specificity</term>
<term>Structure-Activity Relationship</term>
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<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Relation structure-activité</term>
<term>Résonance magnétique nucléaire biomoléculaire</term>
<term>Simulation de docking moléculaire</term>
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<front><div type="abstract" xml:lang="en">Illustrated here is the development of a new class of antibiotic lead molecules targeted at <i>Pseudomonas aeruginosa</i>
 glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable.</div>
</front>
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<Title>Molecules (Basel, Switzerland)</Title>
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<ArticleTitle>Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.</ArticleTitle>
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<Abstract><AbstractText>Illustrated here is the development of a new class of antibiotic lead molecules targeted at <i>Pseudomonas aeruginosa</i>
 glutaredoxin (PaGRX). This lead was produced to (a) circumvent efflux-mediated resistance mechanisms via covalent inhibition while (b) taking advantage of species selectivity to target a fundamental metabolic pathway. This work involved four components: a novel workflow for generating protein specific fragment hits via independent nuclear magnetic resonance (NMR) measurements, NMR-based modeling of the target protein structure, NMR guided docking of hits, and synthetic modification of the fragment hit with a vinyl cysteine trap moiety, i.e., acrylamide warhead, to generate the chimeric lead. Reactivity of the top warhead-fragment lead suggests that the ortholog selectivity observed for a fragment hit can translate into a substantial kinetic advantage in the mature warhead lead, which bodes well for future work to identify potent, species specific drug molecules targeted against proteins heretofore deemed undruggable.</AbstractText>
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<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Khattri</LastName>
<ForeName>Ram B</ForeName>
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<AffiliationInfo><Affiliation>Department of Physiology and Functional genomics, University of Florida, Gainesville, FL 32610, USA.</Affiliation>
</AffiliationInfo>
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</AffiliationInfo>
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<ForeName>Stephanie M</ForeName>
<Initials>SM</Initials>
<AffiliationInfo><Affiliation>Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA.</Affiliation>
</AffiliationInfo>
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</AffiliationInfo>
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<Initials>JW</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry, The University of Akron, Akron, OH 44325, USA.</Affiliation>
</AffiliationInfo>
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<ForeName>David A</ForeName>
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<AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry, The University of Akron, Akron, OH 44325, USA.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Leeper</LastName>
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Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.

Identifying Ortholog Selective Fragment Molecules for Bacterial Glutaredoxins by NMR and Affinity Enhancement by Modification with an Acrylamide Warhead.

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