Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure

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Chimed Jansen, Huanchen Wang, Albert J. Kooistra, Chris De Graaf, Kristina M. Orrling, Hermann Tenor, Thomas Seebeck, David Bailey, Iwan J.P. De Esch, Hengming Ke, Rob Leurs

Trypanosoma brucei cyclic nucleotide phosphodiesterase B1 (TbrPDEB1) and TbrPDEB2 have recently been validated as new therapeutic targets for human African trypanosomiasis by both genetic and pharmacological means. In this study we report the crystal structure of the catalytic domain of the unliganded TbrPDEB1 and its use for the in silico screening for new TbrPDEB1 inhibitors with novel scaffolds. The TbrPDEB1 crystal structure shows the characteristic folds of human PDE enzymes but also contains the parasite-specific P-pocket found in the structures of Leishmania major PDEB1 and Trypanosoma cruzi PDEC. The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. This approach identified six novel TbrPDEB1 inhibitors with IC50 values of 10-80 μM, which may be further optimized as potential selective TbrPDEB inhibitors.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume56
Issue number5
Pages (from-to)2087-2096
Number of pages10
ISSN0022-2623
DOIs
Publication statusPublished - 14 Mar 2013
Externally publishedYes

ID: 199376294