Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 5, Pages 2087-2096Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3017877
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Funding
- NIH Grant [GM59791]
- Top Institute Pharma Project Phosphodiesterase Inhibitors for Neglected Tropical Diseases [T4-302]
- VU University Amsterdam
- University of Bern
- Royal Tropical Institute (KIT)
- Mercachem BV
- Nycomed (a Takeda company)
- IOTA Pharmaceuticals Ltd.
- Drugs for Neglected Diseases Initiative (DNDi)
- TI Pharma
- The Netherlands Organization for Scientific Research (NWO) through a VENI Grant [700.59.408]
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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 mu M, which may be further optimized as potential selective TbrPDEB inhibitors.
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