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

C. Jansen, H. Wang, A.J. Kooistra, C. de Graaf, K.M. Orrling, H. Tenor, T. Seebeck, I.J.P. de Esch, H. Ke, R. Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

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 IC
Original languageEnglish
Pages (from-to)2087-2096
JournalJournal of Medicinal Chemistry
Volume2013
Issue number56
DOIs
Publication statusPublished - 2013

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Trypanosoma brucei brucei
Phosphodiesterase Inhibitors
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Computer Simulation
Molecular Docking Simulation
African Trypanosomiasis
Leishmania major
Trypanosoma cruzi
Dermatoglyphics
Trypanosoma brucei PDEB1 protein
Catalytic Domain
Parasites
Research Design
X-Rays
Pharmacology
Ligands
Enzymes
Proteins

Cite this

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. / Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. In: Journal of Medicinal Chemistry. 2013 ; Vol. 2013, No. 56. pp. 2087-2096.
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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 IC",
author = "C. Jansen and H. Wang and A.J. Kooistra and {de Graaf}, C. and K.M. Orrling and H. Tenor and T. Seebeck and {de Esch}, I.J.P. and H. Ke and R. Leurs",
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Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. / 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.

In: Journal of Medicinal Chemistry, Vol. 2013, No. 56, 2013, p. 2087-2096.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Jansen, C.

AU - Wang, H.

AU - Kooistra, A.J.

AU - de Graaf, C.

AU - Orrling, K.M.

AU - Tenor, H.

AU - Seebeck, T.

AU - de Esch, I.J.P.

AU - Ke, H.

AU - Leurs, R.

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AB - 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 IC

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