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

Authors :: 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
Source :: Future medicinal chemistry [Future Med Chem] 2019 Jul; Vol. 11 (14), pp. 1703-1720. Date of Electronic Publication: 2019 Aug 02.
Publication Year :: 2019
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.

Subjects :: Animals
Dose-Response Relationship, Drug
Models, Molecular
Molecular Structure
Phosphodiesterase 4 Inhibitors chemistry
Schistosomiasis metabolism
Structure-Activity Relationship
Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
Drug Discovery
Phosphodiesterase 4 Inhibitors pharmacology
Schistosoma mansoni enzymology
Schistosomiasis drug therapy

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