Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis Thymidylate Synthase-Dihydrofolate Reductase
Identifieur interne : 001737 ( Pmc/Curation ); précédent : 001736; suivant : 001738Structural 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.
Abstract
Url:
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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<author><name sortKey="Jorgensen, William L" sort="Jorgensen, William L" uniqKey="Jorgensen W" first="William L." last="Jorgensen">William L. Jorgensen</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structural studies provide clues for analog design of specific inhibitors of <italic>Cryptosporidium hominis</italic>
Thymidylate Synthase-Dihydrofolate Reductase</title>
<author><name sortKey="Kumar, Vidya P" sort="Kumar, Vidya P" uniqKey="Kumar V" first="Vidya P." last="Kumar">Vidya P. Kumar</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</wicri:regionArea>
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<author><name sortKey="Cisneros, Jose A" sort="Cisneros, Jose A" uniqKey="Cisneros J" first="Jose A." last="Cisneros">Jose A. Cisneros</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107</wicri:regionArea>
</affiliation>
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<author><name sortKey="Frey, Kathleen M" sort="Frey, Kathleen M" uniqKey="Frey K" first="Kathleen M." last="Frey">Kathleen M. Frey</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</wicri:regionArea>
</affiliation>
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<author><name sortKey="Castellanos Gonzalez, Alejandro" sort="Castellanos Gonzalez, Alejandro" uniqKey="Castellanos Gonzalez A" first="Alejandro" last="Castellanos-Gonzalez">Alejandro Castellanos-Gonzalez</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston</wicri:regionArea>
</affiliation>
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<author><name sortKey="Wang, Yiqiang" sort="Wang, Yiqiang" uniqKey="Wang Y" first="Yiqiang" last="Wang">Yiqiang Wang</name>
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<wicri:regionArea>Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282</wicri:regionArea>
</affiliation>
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<author><name sortKey="Gangjee, Aleem" sort="Gangjee, Aleem" uniqKey="Gangjee A" first="Aleem" last="Gangjee">Aleem Gangjee</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282</wicri:regionArea>
</affiliation>
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<author><name sortKey="White, A Clinton" sort="White, A Clinton" uniqKey="White A" first="A. Clinton" last="White">A. Clinton White</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston</wicri:regionArea>
</affiliation>
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<author><name sortKey="Jorgensen, William L" sort="Jorgensen, William L" uniqKey="Jorgensen W" first="William L." last="Jorgensen">William L. Jorgensen</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Anderson, Karen S" sort="Anderson, Karen S" uniqKey="Anderson K" first="Karen S." last="Anderson">Karen S. Anderson</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</wicri:regionArea>
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<series><title level="j">Bioorganic & medicinal chemistry letters</title>
<idno type="ISSN">0960-894X</idno>
<idno type="eISSN">1464-3405</idno>
<imprint><date when="2014">2014</date>
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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>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9107377</journal-id>
<journal-id journal-id-type="pubmed-jr-id">20409</journal-id>
<journal-id journal-id-type="nlm-ta">Bioorg Med Chem Lett</journal-id>
<journal-id journal-id-type="iso-abbrev">Bioorg. Med. Chem. Lett.</journal-id>
<journal-title-group><journal-title>Bioorganic & medicinal chemistry letters</journal-title>
</journal-title-group>
<issn pub-type="ppub">0960-894X</issn>
<issn pub-type="epub">1464-3405</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25127103</article-id>
<article-id pub-id-type="pmc">4427026</article-id>
<article-id pub-id-type="doi">10.1016/j.bmcl.2014.07.049</article-id>
<article-id pub-id-type="manuscript">NIHMS661090</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Structural studies provide clues for analog design of specific inhibitors of <italic>Cryptosporidium hominis</italic>
Thymidylate Synthase-Dihydrofolate Reductase</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Vidya P.</given-names>
</name>
<xref ref-type="aff" rid="A1">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cisneros</surname>
<given-names>Jose A.</given-names>
</name>
<xref ref-type="aff" rid="A2">b</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Frey</surname>
<given-names>Kathleen M.</given-names>
</name>
<xref ref-type="aff" rid="A1">a</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Castellanos-Gonzalez</surname>
<given-names>Alejandro</given-names>
</name>
<xref ref-type="aff" rid="A3">c</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Yiqiang</given-names>
</name>
<xref ref-type="aff" rid="A4">d</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gangjee</surname>
<given-names>Aleem</given-names>
</name>
<xref ref-type="aff" rid="A4">d</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>White</surname>
<given-names>A. Clinton</given-names>
<suffix>Jr</suffix>
</name>
<xref ref-type="aff" rid="A3">c</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jorgensen</surname>
<given-names>William L.</given-names>
</name>
<xref ref-type="aff" rid="A2">b</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Anderson</surname>
<given-names>Karen S.</given-names>
</name>
<xref ref-type="aff" rid="A1">a</xref>
<xref ref-type="corresp" rid="CR1">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>a</label>
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA</aff>
<aff id="A2"><label>b</label>
Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107, USA</aff>
<aff id="A3"><label>c</label>
Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA</aff>
<aff id="A4"><label>d</label>
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA</aff>
<author-notes><corresp id="CR1"><label>*</label>
Corresponding authors. Tel. +1 203 785 4526, fax. +1 203 785 7670 (KSA); Tel. +1 203 432 6278, fax. +1 203 432 6299 (WLJ); Tel: +1 412 396 6070, fax: +1 412 396 5593 (AG). <email>karen.anderson@yale.edu</email>
; <email>william.jorgensen@yale.edu</email>
; <email>gangjee@duq.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>4</day>
<month>5</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>24</day>
<month>7</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="ppub"><day>1</day>
<month>9</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>11</day>
<month>5</month>
<year>2015</year>
</pub-date>
<volume>24</volume>
<issue>17</issue>
<fpage>4158</fpage>
<lpage>4161</lpage>
<pmc-comment>elocation-id from pubmed: 10.1016/j.bmcl.2014.07.049</pmc-comment>
<abstract><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>
</abstract>
<kwd-group><kwd>Thymidylate synthase</kwd>
<kwd>Cryptosporidium</kwd>
<kwd>Inhibitor</kwd>
<kwd>Dihydrofolate reductase</kwd>
<kwd>Crystal structure</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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