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.

In-silico Identification of Candidate Inhibitory Ligands against Ornithine Decarboxylase Enzyme for Human Sleeping Sickness Causing Trypanosoma brucei

“…The ZINC database screening revealed inhibitor ligands against phosphodiesterase B1 and B2 enzymes to suppress T. brucei based on virtual screening methods [17]. The contemporary study also revealed potential inhibitory ligands (ZINC01703953 and ZINC67855534) for ornithine decarboxylase (ODC) enzyme.…”

“…Hence, alternative drug targets identification is indispensable. Hence, ZINC database can be used for virtual screening (VS) experiment to identify the potential inhibitory ligands for polyamine biosynthetic pathway enzymes of T. brucei [17]. ZINC database is a free chemical database, consisting of nearly 13 million small commercially available molecules [18].…”

“…The molecular modeling of the proteins and their interactions with the ligands is a bottleneck issue in deciding the functionality of the proteins within the biological systems. Novel inhibitors were identified through virtual screening of ligands from ZINC database against the new therapeutic targets of T. brucei, such as cyclic nucleotide phosphodiesterase (TbrPDEB1 and TbrPDEB2) [17].…”

Repurposing human PDE4 inhibitors for neglected tropical diseases: Design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors

“…We also wished to determine whether a stereochemically simplified headgroup replacement could be achieved. Secondly, a key structural feature of the TbrPDEB1 binding site, predicted by homology modeling and confirmed by crystallography, 5, 15 is a pocket adjacent to the binding site (termed the “parasite-“ or “Ppocket”) that is deeper in comparison to the same region in hPDE4. Thus, guided by the SAR studies of the catechol diethers 2 and 3 reported previously that were intended to explore the “parasite pocket” of the enzyme, we now report exploration of the cyclopentyl ether (Figure 1, red) to longer, chain-extended versions, and we then studied the protein-ligand interactions in silico by carrying out molecular docking using the recently published crystal structure of TbrPDEB1.…”

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

“…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];…”