Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Wang, Huanchen; Kunz, Stefan; Chen, Gong; Seebeck, Thomas; Wan, Yiqian; Robinson, Howard; Martinelli, Sibylla; Ke, Hengming

doi:10.1074/jbc.m111.326777

Cited by 30 publications

(42 citation statements)

References 52 publications

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“…The structural superposition of TbrPDEB1 with LmjPDEB1 (2R8Q), 12 TcrPDEC (3V94) 4 and hPDE4B (1XM4) 17 yielded RMSDs of 0.86 Å, 1.78 Å and 1.61 Å respectively for comparable Cα atoms (Figure 2B), indicating high overall structural similarity. Taking a closer look at the region between the Q874 and the M-loop it is clear that the P-pockets of TbrPDEB1 and LmjPDEB1 overlap well.…”

Section: Resultsmentioning

confidence: 98%

“…Moreover, the full length TcrPDEC does not contain GAF domains and has been shown to have a dual specificity for cAMP and cGMP, further indicating its evolutionary distance from TbrPDEB1. 4, 13, 18 The high sequence identity of TbrPDEB1 and LmjPDEB1 on the other hand, suggests that a single compound may well inhibit both parasite PDEs and might be useful against both kinetoplastids.…”

Section: Resultsmentioning

confidence: 99%

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Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

Jansen¹,

Wang

Kooistra³

et al. 2013

J. Med. Chem.

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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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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

Jansen¹,

Wang

Kooistra³

et al. 2013

J. Med. Chem.

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“…Sequence alignment reveals that the gating residues vary significantly across PDE families (Fig. 4C), thus making the pocket inaccessible in many human PDEs (Wang et al, 2007b(Wang et al, , 2012. In addition, the M-loop shows significant differences in sequence and conformations (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

et al. 2015

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Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S), has an IC 50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

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“…Oxoacyl acyl-carrier-protein reductase (OAR) 2C07 [198] Peptide deformylase (PDF) 1JYM [199]; 1RL4, 1RQC [200] Peroxisomal targeting signal 1 (PTS1) 3CV0, 3CVL, CVN, 3CVP, 3CVQ [201] Peroxisomal targeting signal 2 (PTS2) 2F2J [110] Phosphethanolamine methyltransferase (PMT) 3UJ6, 3UJ7, 3UJ8, 3UJ9, 3UJA, 3UJB [202] Phosphodiesterase B1 (PDEB1) 2R8Q [203] 4I15 [204] Phosphodiesterase C (PDEC) 3V93 [205]; 3V94 [206] Phosphoenolpyruvate carboxykinase (PEPCH) 1II2 [207] Phosphofructokinase (PFK) 3F5M [208] 6-Phosphoglucolactonase (6PGL) 2J0E [209]; 3E7F, 3EB9 [210] 6-Phosphogluconate dehydrogenase (6PGDH) 1PGJ [211] Phosphoglucose isomerase (PGI) 1Q50, 1T10 [212] 2O2C, 2O2D [213] Phosphoglycerate kinase (PGK) 3OZA, 3OZ7 [214] 13PK [215]; 16PK [216] Phosphoglycerate mutase (PGAM) 3IGY, 3IGZ [217] 3EOZ [218] 3NVL [219] [220] 3F9R [221] Plasmepsin I (PMI) 2R9B [222]; 3QRV, 3QS1 [223];…”

Section: Brucei T Cruzimentioning

confidence: 99%

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

Ogungbe

Setzer

2016

Molecules

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Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp.

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Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Cited by 30 publications

References 52 publications

Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

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