ArticleJournal of medicinal chemistry2013
Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 52 citations in OpenAlex.
- Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.Journal of medicinal chemistry · 2023Article
- To Target or Not to TargetInternational journal of molecular sciences · 2023Article
- Exploring the Activity Profile of TbrPDEB1 and hPDE4 Inhibitors Using Free Energy Perturbation.ACS medicinal chemistry letters · 2022Article
- G Protein-Coupled Receptors as Potential Intercellular Communication Mediators in Trypanosomatidae.Frontiers in cellular and infection microbiology · 2022Review
- Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages.PLoS neglected tropical diseases · 2020Article
- Methods to Investigate Signal Transduction Pathways in Trypanosoma cruzi: Cyclic Nucleotide Phosphodiesterases Assay Protocols.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening.Frontiers in chemistry · 2020Article
- Identification ofGenes · 2019Article
- Imidazole Derivatives as Promising Agents for the Treatment of Chagas Disease.Antimicrobial agents and chemotherapy · 2019Article
- Druggable Targets in Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites and Kinetoplastids against Disabling Protozoan Diseases in Humans.International journal of molecular sciences · 2019Review
- Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.Journal of medicinal chemistry · 2018Article
- Adenylate Cyclases ofPathogens (Basel, Switzerland) · 2018Review
- The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target.PLoS neglected tropical diseases · 2017Article
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- Function-specific virtual screening for GPCR ligands using a combined scoring method.Scientific reports · 2016Article
- Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting.Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases · 2016Article
- cAMP signalling in trypanosomatids: role in pathogenesis and as a drug target.Trends in parasitology · 2015Review
- Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei.Chemical biology & drug design · 2015Article
- Hierarchical virtual screening approaches in small molecule drug discovery.Methods (San Diego, Calif.) · 2015Review
- The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!Frontiers in pharmacology · 2015Review
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Authors and funding
11 authors at 3 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.