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

Chimed Jansen; Huanchen Wang; Albert J. Kooistra; Chris De Graaf; Kristina M. Orrling; Hermann Tenor; Thomas Seebeck; David Bailey; Iwan J.P. De Esch; Hengming Ke; Rob Leurs

doi:10.1021/jm3017877

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

Chimed Jansen, Huanchen Wang, Albert J. Kooistra, Chris De Graaf, Kristina M. Orrling, Hermann Tenor, Thomas Seebeck, David Bailey, Iwan J.P. De Esch, Hengming Ke^*, Rob Leurs

^*Corresponding author af dette arbejde

45 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	56
Udgave nummer	5
Sider (fra-til)	2087-2096
Antal sider	10
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm3017877
Status	Udgivet - 14 mar. 2013
Udgivet eksternt	Ja

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Jansen, C., Wang, H., Kooistra, A. J., De Graaf, C., Orrling, K. M., Tenor, H., Seebeck, T., Bailey, D., 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, 56(5), 2087-2096. https://doi.org/10.1021/jm3017877

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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.",

author = "Chimed Jansen and Huanchen Wang and Kooistra, {Albert J.} and {De Graaf}, Chris and Orrling, {Kristina M.} and Hermann Tenor and Thomas Seebeck and David Bailey and {De Esch}, {Iwan J.P.} and Hengming Ke and Rob Leurs",

year = "2013",

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doi = "10.1021/jm3017877",

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AU - Jansen, Chimed

AU - Wang, Huanchen

AU - Kooistra, Albert J.

AU - De Graaf, Chris

AU - Orrling, Kristina M.

AU - Tenor, Hermann

AU - Seebeck, Thomas

AU - Bailey, David

AU - De Esch, Iwan J.P.

AU - Ke, Hengming

AU - Leurs, Rob

PY - 2013/3/14

Y1 - 2013/3/14

N2 - 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.

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 IC50 values of 10-80 μM, which may be further optimized as potential selective TbrPDEB inhibitors.

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

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