Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure
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Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. / Jansen, Chimed; Wang, Huanchen; Kooistra, Albert J.; De Graaf, Chris; Orrling, Kristina M.; Tenor, Hermann; Seebeck, Thomas; Bailey, David; De Esch, Iwan J.P.; Ke, Hengming; Leurs, Rob.
In: Journal of Medicinal Chemistry, Vol. 56, No. 5, 14.03.2013, p. 2087-2096.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 56
SP - 2087
EP - 2096
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -
ID: 199376294