title: Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.
abstract: 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.
authors: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
authors: Chimed
authors: C
authors: Jansen
authors: Huanchen
authors: H
authors: Wang
authors: Albert J
authors: AJ
authors: Kooistra
authors: Chris
authors: C
authors: de Graaf
authors: Kristina M
authors: KM
authors: Orrling
authors: Hermann
authors: H
authors: Tenor
authors: Thomas
authors: T
authors: Seebeck
authors: David
authors: D
authors: Bailey
authors: Iwan J P
authors: IJ
authors: de Esch
authors: Hengming
authors: H
authors: Ke
authors: Rob
authors: R
authors: Leurs
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D003460:Crystallization; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000302:isolation & purification* / Q000627:therapeutic use; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D016415:Sequence Alignment; D014346:Trypanosoma brucei brucei / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy; D014961:X-Ray Diffraction
chemical_list: D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D015800:Protozoan Proteins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C581006:PDEB1 protein, Trypanosoma brucei