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 for this work

45 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	5
Pages (from-to)	2087-2096
Number of pages	10
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm3017877
Publication status	Published - 14 Mar 2013
Externally published	Yes

Access to Document

10.1021/jm3017877

Cite this

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

Jansen, C, Wang, H, Kooistra, AJ, De Graaf, C, Orrling, KM, Tenor, H, Seebeck, T, Bailey, D, De Esch, IJP, 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. 56, no. 5, pp. 2087-2096. https://doi.org/10.1021/jm3017877

@article{99951a9c86654ef9a546e827d864d061,

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",

month = mar,

day = "14",

doi = "10.1021/jm3017877",

language = "English",

volume = "56",

pages = "2087--2096",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "5",

}

TY - JOUR

T1 - Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure

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.

UR - http://www.scopus.com/inward/record.url?scp=84875151295&partnerID=8YFLogxK

U2 - 10.1021/jm3017877

DO - 10.1021/jm3017877

M3 - Journal article

C2 - 23409953

AN - SCOPUS:84875151295

SN - 0022-2623

VL - 56

SP - 2087

EP - 2096

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this