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

Víctor Sebastián-Pérez, Susanne Schroeder, Jane C. Munday, Tiffany Van Der Meer, Josefa Zaldívar-Díez, Marco Siderius, Harry P. De Koning, Dave Brown, Ana Martínez, Nuria E. Campillo, Rob Leurs, Carmen Gil

Research output: Contribution to JournalArticleAcademicpeer-review

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 & 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 & 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.

Original languageEnglish
Pages (from-to)1703-1720
Number of pages18
JournalFuture Medicinal Chemistry
Volume11
Issue number14
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

Schistosoma mansoni
Schistosomiasis
Phosphoric Diester Hydrolases
Small Molecule Libraries
Cyclic Nucleotides
Libraries
Enzymes
Pharmaceutical Preparations

Keywords

  • inhibitors
  • phosphodiesterase
  • schistosomiasis
  • virtual screening

Cite this

Sebastián-Pérez, V., Schroeder, S., Munday, J. C., Van Der Meer, T., Zaldívar-Díez, J., Siderius, M., ... Gil, C. (2019). Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. Future Medicinal Chemistry, 11(14), 1703-1720. https://doi.org/10.4155/fmc-2018-0592
Sebastián-Pérez, Víctor ; Schroeder, Susanne ; Munday, Jane C. ; Van Der Meer, Tiffany ; Zaldívar-Díez, Josefa ; Siderius, Marco ; De Koning, Harry P. ; Brown, Dave ; Martínez, Ana ; Campillo, Nuria E. ; Leurs, Rob ; Gil, Carmen. / Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. In: Future Medicinal Chemistry. 2019 ; Vol. 11, No. 14. pp. 1703-1720.
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Sebastián-Pérez, V, Schroeder, S, Munday, JC, Van Der Meer, T, Zaldívar-Díez, J, Siderius, M, De Koning, HP, Brown, D, Martínez, A, Campillo, NE, Leurs, R & Gil, C 2019, 'Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis' Future Medicinal Chemistry, vol. 11, no. 14, pp. 1703-1720. https://doi.org/10.4155/fmc-2018-0592

Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. / Sebastián-Pérez, Víctor; Schroeder, Susanne; Munday, Jane C.; Van Der Meer, Tiffany; Zaldívar-Díez, Josefa; Siderius, Marco; De Koning, Harry P.; Brown, Dave; Martínez, Ana; Campillo, Nuria E.; Leurs, Rob; Gil, Carmen.

In: Future Medicinal Chemistry, Vol. 11, No. 14, 01.01.2019, p. 1703-1720.

Research output: Contribution to JournalArticleAcademicpeer-review

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Sebastián-Pérez V, Schroeder S, Munday JC, Van Der Meer T, Zaldívar-Díez J, Siderius M et al. Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. Future Medicinal Chemistry. 2019 Jan 1;11(14):1703-1720. https://doi.org/10.4155/fmc-2018-0592