Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design

作者：Howard Brittany L; Thompson Philip E; M****lack David T^*

来源：Journal of Computer-Aided Molecular Design, 2011, 25(8): 753-762.

DOI：10.1007/s10822-011-9458-5

• Malaria
• Plasmodium falciparum
• Phosphodiesterase
• Homology modelling
• Molecular modelling
• Molecular docking

The similarity between Plasmodium falciparum phosphodiesterase enzymes (PfPDEs) and their human counterparts have been examined and human PDE9A was found to be a suitable template for the construction of homology models for each of the four PfPDE isoforms. In contrast, the architecture of the active sites of each model was most similar to human PDE1. Molecular docking was able to model cyclic guanosine monophosphate (cGMP) substrate binding in each case but a docking mode supporting cyclic adenosine monophosphate (cAMP) binding could not be found. Anticipating the potential of PfPDE inhibitors as anti-malarial drugs, a range of reported PDE inhibitors including zaprinast and sildenafil were docked into the model of PfPDE alpha. The results were consistent with their reported biological activities, and the potential of PDE1/9 inhibitor analogues was also supported by docking.

• 出版日期2011-8