PittsburghV1, Main, Curation, bibRecord, 001146

Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase

Identifieur interne : 001146 ( Main/Curation ); précédent : 001145; suivant : 001147

Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase

Auteurs : Vidya P. Kumar [États-Unis] ; Jose A. Cisneros [États-Unis] ; Kathleen M. Frey [États-Unis] ; Alejandro Castellanos-Gonzalez [États-Unis] ; Yiqiang Wang [États-Unis] ; Aleem Gangjee [États-Unis] ; A. Clinton White [États-Unis] ; William L. Jorgensen [États-Unis] ; Karen S. Anderson [États-Unis]

Source :

Bioorganic & medicinal chemistry letters [ 0960-894X ] ; 2014.

RBID : PMC:4427026

Descripteurs français

KwdFr :
- Antienzymes (), Antienzymes (pharmacologie), Antienzymes (synthèse chimique), Complexes multienzymatiques (antagonistes et inhibiteurs), Complexes multienzymatiques (métabolisme), Conception de médicament, Cryptosporidium (enzymologie), Dihydrofolate reductase (métabolisme), Modèles moléculaires, Pyrimidines (), Pyrimidines (pharmacologie), Pyrimidines (synthèse chimique), Pyrroles (), Pyrroles (pharmacologie), Pyrroles (synthèse chimique), Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire, Thymidylate synthase (antagonistes et inhibiteurs), Thymidylate synthase (métabolisme).
MESH :
- antagonistes et inhibiteurs : Complexes multienzymatiques, Thymidylate synthase.
- enzymologie : Cryptosporidium.
- métabolisme : Complexes multienzymatiques, Dihydrofolate reductase, Thymidylate synthase.
- pharmacologie : Antienzymes, Pyrimidines, Pyrroles.
- synthèse chimique : Antienzymes, Pyrimidines, Pyrroles.
- Antienzymes, Conception de médicament, Modèles moléculaires, Pyrimidines, Pyrroles, Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire.

English descriptors

KwdEn :
- Cryptosporidium (enzymology), Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors (chemical synthesis), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Models, Molecular, Molecular Structure, Multienzyme Complexes (antagonists & inhibitors), Multienzyme Complexes (metabolism), Pyrimidines (chemical synthesis), Pyrimidines (chemistry), Pyrimidines (pharmacology), Pyrroles (chemical synthesis), Pyrroles (chemistry), Pyrroles (pharmacology), Structure-Activity Relationship, Tetrahydrofolate Dehydrogenase (metabolism), Thymidylate Synthase (antagonists & inhibitors), Thymidylate Synthase (metabolism).
MESH :
- chemical , antagonists & inhibitors : Multienzyme Complexes, Thymidylate Synthase.
- chemical , chemical synthesis : Enzyme Inhibitors, Pyrimidines, Pyrroles.
- chemical , chemistry : Enzyme Inhibitors, Pyrimidines, Pyrroles.
- enzymology : Cryptosporidium.
- chemical , metabolism : Multienzyme Complexes, Tetrahydrofolate Dehydrogenase, Thymidylate Synthase.
- chemical , pharmacology : Enzyme Inhibitors, Pyrimidines, Pyrroles.
- Dose-Response Relationship, Drug, Drug Design, Models, Molecular, Molecular Structure, Structure-Activity Relationship.

Abstract

Cryptosporidium is the causative agent of a gastrointestinal disease, cryptosporidiosis, which is often fatal in immunocompromised individuals and children. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer, bacterial infections, and malaria. Cryptosporidium hominis has a bifunctional thymidylate synthase and dihydrofolate reductase enzyme, compared to separate enzymes in the host. We evaluated lead compound 1 from a novel series of antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines as an inhibitor of Cryptosporidium hominis thymidylate synthase with selectivity over the human enzyme. Complementing the enzyme inhibition compound 1 also has anti-cryptosporidial activity in cell culture. A crystal structure with compound 1 bound to the TS active site is discussed in terms of several van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate (TS), cofactor NADPH and inhibitor methotrexate (DHFR). Another crystal structure in complex with compound 1 bound in both the TS and DHFR active sites is also reported here. The crystal structures provide clues for analog design and for the design of ChTS-DHFR specific inhibitors.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427026

DOI: 10.1016/j.bmcl.2014.07.049
PubMed: 25127103
PubMed Central: 4427026

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 Thymidylate Synthase-Dihydrofolate Reductase</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cryptosporidium (enzymology)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Enzyme Inhibitors (chemical synthesis)</term>
<term>Enzyme Inhibitors (chemistry)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Multienzyme Complexes (antagonists & inhibitors)</term>
<term>Multienzyme Complexes (metabolism)</term>
<term>Pyrimidines (chemical synthesis)</term>
<term>Pyrimidines (chemistry)</term>
<term>Pyrimidines (pharmacology)</term>
<term>Pyrroles (chemical synthesis)</term>
<term>Pyrroles (chemistry)</term>
<term>Pyrroles (pharmacology)</term>
<term>Structure-Activity Relationship</term>
<term>Tetrahydrofolate Dehydrogenase (metabolism)</term>
<term>Thymidylate Synthase (antagonists & inhibitors)</term>
<term>Thymidylate Synthase (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antienzymes ()</term>
<term>Antienzymes (pharmacologie)</term>
<term>Antienzymes (synthèse chimique)</term>
<term>Complexes multienzymatiques (antagonistes et inhibiteurs)</term>
<term>Complexes multienzymatiques (métabolisme)</term>
<term>Conception de médicament</term>
<term>Cryptosporidium (enzymologie)</term>
<term>Dihydrofolate reductase (métabolisme)</term>
<term>Modèles moléculaires</term>
<term>Pyrimidines ()</term>
<term>Pyrimidines (pharmacologie)</term>
<term>Pyrimidines (synthèse chimique)</term>
<term>Pyrroles ()</term>
<term>Pyrroles (pharmacologie)</term>
<term>Pyrroles (synthèse chimique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
<term>Thymidylate synthase (antagonistes et inhibiteurs)</term>
<term>Thymidylate synthase (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Multienzyme Complexes</term>
<term>Thymidylate Synthase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Complexes multienzymatiques</term>
<term>Thymidylate synthase</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Cryptosporidium</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Cryptosporidium</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Multienzyme Complexes</term>
<term>Tetrahydrofolate Dehydrogenase</term>
<term>Thymidylate Synthase</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexes multienzymatiques</term>
<term>Dihydrofolate reductase</term>
<term>Thymidylate synthase</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antienzymes</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Models, Molecular</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
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<term>Conception de médicament</term>
<term>Modèles moléculaires</term>
<term>Pyrimidines</term>
<term>Pyrroles</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Structure moléculaire</term>
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<front><div type="abstract" xml:lang="en"><p id="P1"><italic>Cryptosporidium</italic>
 is the causative agent of a gastrointestinal disease, cryptosporidiosis, which is often fatal in immunocompromised individuals and children. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer, bacterial infections, and malaria. <italic>Cryptosporidium hominis</italic>
 has a bifunctional thymidylate synthase and dihydrofolate reductase enzyme, compared to separate enzymes in the host. We evaluated lead compound <bold>1</bold>
 from a novel series of antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-<italic>d</italic>
]pyrimidines as an inhibitor of <italic>Cryptosporidium hominis</italic>
 thymidylate synthase with selectivity over the human enzyme. Complementing the enzyme inhibition compound <bold>1</bold>
 also has anti-cryptosporidial activity in cell culture. A crystal structure with compound <bold>1</bold>
 bound to the TS active site is discussed in terms of several van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate (TS), cofactor NADPH and inhibitor methotrexate (DHFR). Another crystal structure in complex with compound <bold>1</bold>
 bound in both the TS and DHFR active sites is also reported here. The crystal structures provide clues for analog design and for the design of <italic>Ch</italic>
TS-DHFR specific inhibitors.</p>
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</record>

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EXPLOR_STEP=$WICRI_ROOT/Wicri/Amérique/explor/PittsburghV1/Data/Main/Curation

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001146 | SxmlIndent | more

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{{Explor lien
   |wiki=    Wicri/Amérique
   |area=    PittsburghV1
   |flux=    Main
   |étape=   Curation
   |type=    RBID
   |clé=     PMC:4427026
   |texte=   Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase
}}

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HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Curation/RBID.i   -Sk "pubmed:25127103" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Curation/biblio.hfd   \
       | NlmPubMed2Wicri -a PittsburghV1

This area was generated with Dilib version V0.6.38.
Data generation: Fri Jun 18 17:37:45 2021. Site generation: Fri Jun 18 18:15:47 2021

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Serveur d'exploration sur Pittsburgh

Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase

Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase

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