Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

• Published in: Journal of medicinal chemistry Vol. 56; no. 5; pp. 2087 - 2096
• Main Authors: Jansen, Chimed, Wang, Huanchen, Kooistra, Albert J, de Graaf, Chris, Orrling, Kristina M, Tenor, Hermann, Seebeck, Thomas, Bailey, David, de Esch, Iwan J. P, Ke, Hengming, Leurs, Rob
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.03.2013
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - chemistry; Amino Acid Sequence; Animals; Catalytic Domain; Crystallization; Drug Discovery; High-Throughput Screening Assays; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Sequence Data; Phosphodiesterase Inhibitors - isolation & purification; Phosphodiesterase Inhibitors - therapeutic use; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Sequence Alignment; Trypanosoma brucei brucei - enzymology; Trypanosomiasis, African - drug therapy; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3017877

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.