Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure
| Autor: | Hermann Tenor, Albert J. Kooistra, Hengming Ke, Kristina M. Orrling, Thomas Seebeck, David S. Bailey, Chris de Graaf, Chimed Jansen, Rob Leurs, Iwan J. P. de Esch, Huanchen Wang |
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| Přispěvatelé: | Medicinal chemistry, AIMMS |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Phosphodiesterase Inhibitors In silico Molecular Sequence Data Trypanosoma brucei brucei Protozoan Proteins Sequence alignment Trypanosoma brucei Ligands Molecular Docking Simulation Article X-Ray Diffraction SDG 3 - Good Health and Well-being Catalytic Domain parasitic diseases Drug Discovery Animals Humans Amino Acid Sequence Trypanosoma cruzi Virtual screening biology Drug discovery Chemistry Phosphodiesterase biology.organism_classification High-Throughput Screening Assays Trypanosomiasis African Biochemistry 3' 5'-Cyclic-AMP Phosphodiesterases Molecular Medicine Crystallization Sequence Alignment |
| Zdroj: | Journal of Medicinal Chemistry, 2013(56), 2087-2096. American Chemical Society Jansen, C, Wang, H, Kooistra, A J, de Graaf, C, Orrling, K M, Tenor, H, Seebeck, T, de Esch, I J P, Ke, H & Leurs, R 2013, ' Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure ', Journal of Medicinal Chemistry, vol. 2013, no. 56, pp. 2087-2096 . https://doi.org/10.1021/jm3017877 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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