Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase

Vidya P. Kumar, Jose A. Cisneros, Kathleen M. Frey, Alejandro Castellanos, Yiqiang Wang, Aleem Gangjee, A. Clinton White, William L. Jorgensen, Karen S. Anderson

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4158-4161
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number17
DOIs
StatePublished - Sep 1 2014

Fingerprint

Cryptosporidium
Thymidylate Synthase
Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Crystal structure
Enzymes
Floxuridine
Lead compounds
Catalytic Domain
Enzyme inhibition
Biosynthesis
Cryptosporidiosis
NADP
Folic Acid
Cell culture
Methotrexate
Gastrointestinal Diseases
Hydrogen bonds
Bacterial Infections
Malaria

Keywords

  • Cryptosporidium
  • Crystal structure
  • Dihydrofolate reductase
  • Inhibitor
  • Thymidylate synthase

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. / Kumar, Vidya P.; Cisneros, Jose A.; Frey, Kathleen M.; Castellanos, Alejandro; Wang, Yiqiang; Gangjee, Aleem; White, A. Clinton; Jorgensen, William L.; Anderson, Karen S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 17, 01.09.2014, p. 4158-4161.

Research output: Contribution to journalArticle

Kumar, Vidya P. ; Cisneros, Jose A. ; Frey, Kathleen M. ; Castellanos, Alejandro ; Wang, Yiqiang ; Gangjee, Aleem ; White, A. Clinton ; Jorgensen, William L. ; Anderson, Karen S. / Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 17. pp. 4158-4161.
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