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

Kumar VP, Cisneros JA, Frey KM, Castellanos-Gonzalez A, Wang Y, Gangjee A, White AC, Jorgensen WL, Anderson KS
Bioorg Med Chem Lett 24 4158-61 (2014)
Cited: 18 times
EuropePMC logo PMID: 25127103

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.

Articles - 4q0e mentioned but not cited (3)

  1. Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. Kumar VP, Cisneros JA, Frey KM, Castellanos-Gonzalez A, Wang Y, Gangjee A, White AC, Jorgensen WL, Anderson KS. Bioorg Med Chem Lett 24 4158-4161 (2014)
  2. Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors. Czyzyk DJ, Valhondo M, Deiana L, Tirado-Rives J, Jorgensen WL, Anderson KS. Eur J Med Chem 183 111673 (2019)
  3. Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase. Czyzyk DJ, Valhondo M, Jorgensen WL, Anderson KS. FEBS Lett 593 2069-2078 (2019)


Reviews citing this publication (5)

  1. Novel treatment strategies and drugs in development for cryptosporidiosis. Chavez MA, White AC. Expert Rev Anti Infect Ther 16 655-661 (2018)
  2. Recent developments in drug discovery against the protozoal parasites Cryptosporidium and Toxoplasma. Chellan P, Sadler PJ, Land KM. Bioorg Med Chem Lett 27 1491-1501 (2017)
  3. Understanding the molecular mechanism of substrate channeling and domain communication in protozoal bifunctional TS-DHFR. Anderson KS. Protein Eng Des Sel 30 253-261 (2017)
  4. Treatment of human intestinal cryptosporidiosis: A review of published clinical trials. Diptyanusa A, Sari IP. Int J Parasitol Drugs Drug Resist 17 128-138 (2021)
  5. Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer. Kumar A, Singh AK, Singh H, Thareja S, Kumar P. Med Oncol 40 3 (2022)

Articles citing this publication (10)

  1. Treatment of Cryptosporidium: What We Know, Gaps, and the Way Forward. Sparks H, Nair G, Castellanos-Gonzalez A, White AC. Curr Trop Med Rep 2 181-187 (2015)
  2. Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors. Alzhrani ZMM, Alam MM, Neamatallah T, Nazreen S. J Enzyme Inhib Med Chem 35 1116-1123 (2020)
  3. A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium. Mukerjee A, Iyidogan P, Castellanos-Gonzalez A, Cisneros JA, Czyzyk D, Ranjan AP, Jorgensen WL, White AC, Vishwanatha JK, Anderson KS. Bioorg Med Chem Lett 25 2065-2067 (2015)
  4. Novel 5-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and as potential antitumor agents. Wang Y, Mitchell-Ryan S, Raghavan S, George C, Orr S, Hou Z, Matherly LH, Gangjee A. J Med Chem 58 1479-1493 (2015)
  5. Synthesis of New 1, 3, 4-Oxadiazole-Incorporated 1, 2, 3-Triazole Moieties as Potential Anticancer Agents Targeting Thymidylate Synthase and Their Docking Studies. Alam MM, Almalki AS, Neamatallah T, Ali NM, Malebari AM, Nazreen S. Pharmaceuticals (Basel) 13 E390 (2020)
  6. Molecular Characteristics and Serodiagnostic Potential of Dihydrofolate Reductase from Echinococcus granulosus. Song X, Hu D, Yan M, Wang Y, Wang N, Gu X, Yang G. Sci Rep 7 514 (2017)
  7. Novel allosteric covalent inhibitors of bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa identified by virtual screening. Ruiz V, Czyzyk DJ, Valhondo M, Jorgensen WL, Anderson KS. Bioorg Med Chem Lett 29 1413-1418 (2019)
  8. Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol. Fekete B, Palkó M, Haukka M, Fülöp F. Molecules 22 E613 (2017)
  9. Targeting the TS dimer interface in bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa: Virtual screening identifies novel TS allosteric inhibitors. Ruiz VG, Czyzyk DJ, Kumar VP, Jorgensen WL, Anderson KS. Bioorg Med Chem Lett 30 127292 (2020)
  10. Crystal structure of dihydrofolate reductase from the filarial nematode W. bancrofti in complex with NADPH and folate. Lange K, Frey KM, Eck T, Janson CA, Gubler U, Goodey NM. PLoS Negl Trop Dis 17 e0011303 (2023)


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