Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase.
Identifieur interne : 001A97 ( PubMed/Curation ); précédent : 001A96; suivant : 001A98Structural 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 [ 1464-3405 ] ; 2014.
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.
DOI: 10.1016/j.bmcl.2014.07.049
PubMed: 25127103
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Jorgensen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107, USA. Electronic address: william.jorgensen@yale.edu.</nlm:affiliation><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:affiliation>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: karen.anderson@yale.edu.</nlm:affiliation><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></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><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></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antienzymes</term><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></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25127103</PMID><DateCreated><Year>2014</Year><Month>08</Month><Day>26</Day></DateCreated><DateCompleted><Year>2015</Year><Month>03</Month><Day>30</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>19</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1464-3405</ISSN><JournalIssue CitedMedium="Internet"><Volume>24</Volume><Issue>17</Issue><PubDate><Year>2014</Year><Month>Sep</Month><Day>01</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry letters</Title><ISOAbbreviation>Bioorg. Med. Chem. Lett.</ISOAbbreviation></Journal><ArticleTitle>Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase.</ArticleTitle><Pagination><MedlinePgn>4158-61</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bmcl.2014.07.049</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0960-894X(14)00773-2</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2014. Published by Elsevier Ltd.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kumar</LastName><ForeName>Vidya P</ForeName><Initials>VP</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cisneros</LastName><ForeName>Jose A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Frey</LastName><ForeName>Kathleen M</ForeName><Initials>KM</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Castellanos-Gonzalez</LastName><ForeName>Alejandro</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Yiqiang</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gangjee</LastName><ForeName>Aleem</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. Electronic address: gangjee@duq.edu.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>White</LastName><ForeName>A Clinton</ForeName><Initials>AC</Initials><Suffix>Jr</Suffix><AffiliationInfo><Affiliation>Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jorgensen</LastName><ForeName>William L</ForeName><Initials>WL</Initials><AffiliationInfo><Affiliation>Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520-8107, USA. Electronic address: william.jorgensen@yale.edu.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Anderson</LastName><ForeName>Karen S</ForeName><Initials>KS</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: karen.anderson@yale.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>GM32136</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI083146</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA152316</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 GM032136</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>CA152316</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>F32 AI104334</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R56 AI083146</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>AI104334</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P41 GM111244</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>AI083146</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>07</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Bioorg Med Chem Lett</MedlineTA><NlmUniqueID>9107377</NlmUniqueID><ISSNLinking>0960-894X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009097">Multienzyme Complexes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011758">Pyrroles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C450639">Pyrrolo(2,3-d)pyrimidine</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C056930">thymidylate synthase-dihydrofolate reductase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.5.1.3</RegistryNumber><NameOfSubstance UI="D013762">Tetrahydrofolate Dehydrogenase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.1.1.45</RegistryNumber><NameOfSubstance UI="D013940">Thymidylate Synthase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>J Antimicrob Chemother. 2000 Jul;46(1):57-60</RefSource><PMID Version="1">10882689</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Chem Pharm Bull (Tokyo). 2001 Oct;49(10):1280-7</RefSource><PMID Version="1">11605654</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Mol Biochem Parasitol. 1996 Aug;79(2):153-65</RefSource><PMID Version="1">8855552</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 Mar 1;61(Pt 3):258-62</RefSource><PMID Version="1">16511011</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Br J Clin Pharmacol. 2007 Apr;63(4):387-93</RefSource><PMID Version="1">17335543</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 2007 Jul 17;46(28):8379-91</RefSource><PMID Version="1">17580969</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 2008 Aug 26;47(34):8902-11</RefSource><PMID Version="1">18672899</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Emerg Infect Dis. 2011 Jan;17(1):7-15</RefSource><PMID Version="1">21192848</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Lancet. 2013 Jul 20;382(9888):209-22</RefSource><PMID Version="1">23680352</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Bioorg Med Chem Lett. 2013 Oct 1;23(19):5426-8</RefSource><PMID Version="1">23927969</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Med Chem. 2013 Dec 27;56(24):10016-32</RefSource><PMID Version="1">24256410</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Lancet Infect Dis. 2015 Jan;15(1):85-94</RefSource><PMID Version="1">25278220</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D003458" MajorTopicYN="N">Cryptosporidium</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004305" MajorTopicYN="N">Dose-Response Relationship, Drug</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="Y">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004791" MajorTopicYN="N">Enzyme Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009097" MajorTopicYN="N">Multienzyme Complexes</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011758" MajorTopicYN="N">Pyrroles</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013762" MajorTopicYN="N">Tetrahydrofolate Dehydrogenase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013940" MajorTopicYN="N">Thymidylate Synthase</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">NIHMS661090</OtherID><OtherID Source="NLM">PMC4427026</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Cryptosporidium</Keyword><Keyword MajorTopicYN="N">Crystal structure</Keyword><Keyword MajorTopicYN="N">Dihydrofolate reductase</Keyword><Keyword MajorTopicYN="N">Inhibitor</Keyword><Keyword MajorTopicYN="N">Thymidylate synthase</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>05</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2014</Year><Month>07</Month><Day>15</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>07</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>8</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>8</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>3</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">25127103</ArticleId><ArticleId IdType="pii">S0960-894X(14)00773-2</ArticleId><ArticleId IdType="doi">10.1016/j.bmcl.2014.07.049</ArticleId><ArticleId IdType="pmc">PMC4427026</ArticleId><ArticleId 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