Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis Articles uri icon

authors

  • SEBASTIÁN-PÉREZ, VÍCTOR
  • SCHROEDER, SUSANNE
  • MUNDAY, JANE C.
  • VAN DER MEER, TIFFANY
  • ZALDIVAR DIEZ DE BONILLA, JOSEFA
  • SIDERIUS, MARCO
  • DE KONING, HARRY P.
  • BROWN, DAVE
  • MARTÍNEZ, ANA
  • MARTINEZ FINKELSHTEIN, ANDREI
  • CAMPILLO, NURIA E.
  • LEURS, ROB
  • GIL, CARMEN

publication date

  • January 2019

start page

  • 1703

end page

  • 1720

issue

  • 14

volume

  • 11

International Standard Serial Number (ISSN)

  • 1756-8919

Electronic International Standard Serial Number (EISSN)

  • 1756-8927

abstract

  • Aim: Due to the urgent need for effective drugs to treat schistosomiasis that act through a known molecular mechanism of action, we focused on a target-based approach with the aim to discover inhibitors of a cyclic nucleotide phosphodiesterase from Schistosoma mansoni (SmPDE4A). Materials and methods: To discover new inhibitors of SmPDE4A homology models of the enzyme structure were constructed based on known human and protozoan homologs. The best two models were selected for subsequent virtual screening of our in-house chemical library. Results and conclusion: A total of 25 library compounds were selected for experimental confirmation as SmPDE4A inhibitors and after dose-response experiments, three top hits were identified. The results presented validate the virtual screening approach to identify new inhibitors for clinically relevant phosphodiesterases.

subjects

  • Biology and Biomedicine

keywords

  • inhibitors; phosphodiesterase; schistosomiasis; virtual screening